Cerebral Vasospasm
Conditions
Keywords
cerebral vasospasm, aneurysmal subarachnoid hemorrhage, intra arterial drug treatment for cerebral vasospasm, nicardipine milrinone nitroglycerin verapamil
Brief summary
The primary objective of the study is to determine the optimal intra-arterial drug treatment regimen for arterial lumen restoration post cerebral vasospasm following aneurysmal subarachnoid hemorrhage. The secondary objective is to evaluate clinical outcome at 90 days post discharge following optimal intra-arterial drug treatment for cerebral vasospasm. We hypothesize that Intra-arterial (IA) infusion of a combination of multiple vasodilators is more efficacious than single agent treatment cerebral vasospasm therapy. All procedures done as a part of this study are standard hospital care procedures done to treat cerebral vasospasm and all drugs to be used are FDA approved.
Detailed description
The primary objective of the study is to determine the optimal intra-arterial drug treatment regimen for arterial lumen restoration post cerebral vasospasm following aneurysmal subarachnoid hemorrhage. The secondary objective is to evaluate clinical outcome at 90 days post discharge following optimal intra-arterial drug treatment for cerebral vasospasm. This study is a prospective multicenter randomized trial. The primary outcome measure is the Post infusion improvement ratio (PIIR) assessed 10 minutes after completion of the intra-arterial infusion. PIIR is a measure of arterial lumen diameter pre and post intra-arterial drug infusion in the presenting vasospasmic blood vessel. Modified Rankin score (mRS) at 3 months post hospital discharge will be recorded as a secondary outcome to assess clinical outcome. The interventions in this study are a part of routine standard of care (SOC) procedures for cerebral vasospasm treatment. Following surgical or endovascular intervention for aneurysmal Subarachnoid Hemorrhage (aSAH) if patients develop cerebral vasospasm refractory to maximal medical management, endovascular treatment by intra-arterial drug infusion of single drug agent or cocktail drug agents will be initiated. Study participants will be randomly assigned to one of the three treatment groups where one single drug agent or cocktail drug agents will be intra-arterially administered. Pre & post infusion vasospasmic vessel diameters will be compared. The change in diameter will be quantified based on the mean percentage change. Three months post hospital discharge, study participants will be followed up in clinic to evaluate clinical outcome. The study will require 330 patients in total. The patient population will be hospitalized patients presenting with cerebral vasospasm post aneurysmal subarachnoid hemorrhage. Subjects will be stratified by randomization into 3 treatment groups.
Interventions
DRUGNicardipine
Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm
DRUGVerapamil
Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm
DRUGNicardipine + Verapamil + Nitroglycerin
Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm
Sponsors
Yale University
Thomas Jefferson University
University of Illinois at Chicago
Wake Forest University Health Sciences
Temple University
Geisinger Clinic
Northwell Health
University of Michigan
Lenox Hill Hospital
Weatherhead Foundation
University of California, Irvine
Peng Roc Chen, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Adult patient, age 18-80 years old, with ruptured aneurysm(s) who experience cerebral vasospasm post operatively within 3-21 days. * Symptomatic vasospasm (clinical or TCD) * For centers that perform a routine day 7 angiogram post-aneurysm treatment - 50% or more stenosis seen on diagnostic angiogram for asymptomatic patients.
Exclusion criteria
* Inability to obtain consent from patient or patients kin * Pregnant women * less than 18 years of age of more than 80 years of age * Hunt Hess Grade 5 SAH * Intra-arterial drug treatment in all 3 arterial territories
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post Infusion Improvement Ratio (PIIR) | pre pharmacological angioplasty blood vessel diameter - 0 min, post pharmacological angioplasty blood vessel diameter- 10 min after infusion | Post infusion improvement ratio (PIIR) = ((B - A) / A) \*100 A = pre-infusion blood vessel diameter B = post infusion blood vessel diameter |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disability or Dependence in Daily Activities as Assessed by the Modified Rankin Score | 3 months post discharge from hospital | The modified Rankin Scale (mRS) is used to assess the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The Modified Rankin Score (mRS) is scored as follows: 0 - No symptoms. 1. \- No significant disability. Able to carry out all usual activities, despite some symptoms. 2. \- Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3. \- Moderate disability. Requires some help, but able to walk unassisted. 4. \- Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5. \- Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6. \- Dead. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Intra-cranial Pressure | 1 day prior to procedure & 1 day after the procedure | Intra-cranial pressure will be measured 1 day prior to vasospasm treatment and 1 day after vasospasm treatment |
Countries
United States
Participant flow
Pre-assignment details
Of 92 enrolled participants, 91 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Nicardipine Group 1 : Nicardipine 5mg per circulation intra-arterial injection, Pharmacological angioplasty
Nicardipine: Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm | 32 |
| Verapamil Group 3: Verapamil 10mg per circulation intra-arterial injection, Pharmacological angioplasty
Verapamil: Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm | 30 |
| Nicardipine + Verapamil + Nitroglycerin Group 4 : Nicardipine 5mg + Verapamil 10mg + Nitroglycerin 200mcg in 4cc 5 % dextrose in water , intra-arterial injection, Pharmacological angioplasty
Nicardipine + Verapamil + Nitroglycerin: Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm | 29 |
| Total | 91 |
Baseline characteristics
| Characteristic | Nicardipine | Verapamil | Nicardipine + Verapamil + Nitroglycerin | Total |
|---|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 13.081 | 50.933 years STANDARD_DEVIATION 13.769 | 50.482 years STANDARD_DEVIATION 10.796 | 51.164 years STANDARD_DEVIATION 12.652 |
| Alcohol History Habitual Alcoholic | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Alcohol History Social Drinker | 7 Participants | 10 Participants | 8 Participants | 25 Participants |
| Alcohol History Teetotaler | 12 Participants | 10 Participants | 12 Participants | 34 Participants |
| Alcohol History Unknown | 11 Participants | 7 Participants | 7 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 5 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 18 Participants | 21 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 5 Participants | 3 Participants | 14 Participants |
| Height | 161.667 centimeters STANDARD_DEVIATION 19.527 | 167.674 centimeters STANDARD_DEVIATION 8.741 | 169.889 centimeters STANDARD_DEVIATION 8.801 | 166.267 centimeters STANDARD_DEVIATION 13.57 |
| Number of Participants with history of diabetes mellitus 1 or 2 | 6 Participants | 4 Participants | 6 Participants | 16 Participants |
| Number of Participants with History of Hypercholesterolemia | 6 Participants | 5 Participants | 3 Participants | 14 Participants |
| Number of Participants with history of hypertension | 17 Participants | 17 Participants | 18 Participants | 52 Participants |
| Number of participants with morbid obesity | 6 Participants | 4 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 5 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 9 Participants | 9 Participants | 28 Participants |
| Race (NIH/OMB) White | 15 Participants | 9 Participants | 14 Participants | 38 Participants |
| Region of Enrollment United States | 32 participants | 30 participants | 29 participants | 92 participants |
| Sex: Female, Male Female | 24 Participants | 21 Participants | 18 Participants | 63 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 11 Participants | 28 Participants |
| Smoking History Current Smoker | 11 Participants | 9 Participants | 12 Participants | 32 Participants |
| Smoking History Non-Smoker | 14 Participants | 16 Participants | 11 Participants | 41 Participants |
| Smoking History Past Smoker | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Smoking History Unknown | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Substance Abuse History Cannabis | 2 Participants | 2 Participants | 4 Participants | 8 Participants |
| Substance Abuse History Cocaine | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Substance Abuse History Crystal Meth | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Substance Abuse History Heroin | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Substance Abuse History No Substance abuse | 21 Participants | 19 Participants | 19 Participants | 59 Participants |
| Substance Abuse History Prescription Drugs | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Substance Abuse History Unknown | 7 Participants | 9 Participants | 6 Participants | 22 Participants |
| Weight | 185.082 pounds (lbs) STANDARD_DEVIATION 50.179 | 166.402 pounds (lbs) STANDARD_DEVIATION 39.156 | 193.338 pounds (lbs) STANDARD_DEVIATION 45.524 | 181.554 pounds (lbs) STANDARD_DEVIATION 45.295 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 32 | 0 / 31 | 3 / 29 |
| other Total, other adverse events | 21 / 32 | 13 / 31 | 27 / 29 |
| serious Total, serious adverse events | 4 / 32 | 0 / 31 | 5 / 29 |
Outcome results
Primary
Post Infusion Improvement Ratio (PIIR)
Post infusion improvement ratio (PIIR) = ((B - A) / A) \*100 A = pre-infusion blood vessel diameter B = post infusion blood vessel diameter
Time frame: pre pharmacological angioplasty blood vessel diameter - 0 min, post pharmacological angioplasty blood vessel diameter- 10 min after infusion
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nicardipine | Post Infusion Improvement Ratio (PIIR) | 51% to 70% | 1 Participants |
| Nicardipine | Post Infusion Improvement Ratio (PIIR) | Below 30% | 4 Participants |
| Nicardipine | Post Infusion Improvement Ratio (PIIR) | Above 70% | 3 Participants |
| Nicardipine | Post Infusion Improvement Ratio (PIIR) | 30% to 50% | 10 Participants |
| Verapamil | Post Infusion Improvement Ratio (PIIR) | 51% to 70% | 6 Participants |
| Verapamil | Post Infusion Improvement Ratio (PIIR) | 30% to 50% | 14 Participants |
| Verapamil | Post Infusion Improvement Ratio (PIIR) | Below 30% | 3 Participants |
| Verapamil | Post Infusion Improvement Ratio (PIIR) | Above 70% | 1 Participants |
| Nicardipine + Verapamil + Nitroglycerin | Post Infusion Improvement Ratio (PIIR) | 30% to 50% | 8 Participants |
| Nicardipine + Verapamil + Nitroglycerin | Post Infusion Improvement Ratio (PIIR) | Below 30% | 2 Participants |
| Nicardipine + Verapamil + Nitroglycerin | Post Infusion Improvement Ratio (PIIR) | Above 70% | 2 Participants |
| Nicardipine + Verapamil + Nitroglycerin | Post Infusion Improvement Ratio (PIIR) | 51% to 70% | 5 Participants |
Secondary
Disability or Dependence in Daily Activities as Assessed by the Modified Rankin Score
The modified Rankin Scale (mRS) is used to assess the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The Modified Rankin Score (mRS) is scored as follows: 0 - No symptoms. 1. \- No significant disability. Able to carry out all usual activities, despite some symptoms. 2. \- Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3. \- Moderate disability. Requires some help, but able to walk unassisted. 4. \- Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5. \- Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6. \- Dead.
Time frame: 3 months post discharge from hospital
Population: Data were not collected from 2 participants from the Nicardipine arm and 5 participants in the Nicardipine + Verapamil + Nitroglycerin arm because the assessment was not administered to them.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicardipine | Disability or Dependence in Daily Activities as Assessed by the Modified Rankin Score | 1.967 score on a scale | Standard Deviation 1.771 |
| Verapamil | Disability or Dependence in Daily Activities as Assessed by the Modified Rankin Score | 1.759 score on a scale | Standard Deviation 1.455 |
| Nicardipine + Verapamil + Nitroglycerin | Disability or Dependence in Daily Activities as Assessed by the Modified Rankin Score | 2.167 score on a scale | Standard Deviation 2.14 |
Other Pre-specified
Intra-cranial Pressure
Intra-cranial pressure will be measured 1 day prior to vasospasm treatment and 1 day after vasospasm treatment
Time frame: 1 day prior to procedure & 1 day after the procedure