Conditions: Cerebral Vasospasm
Keywords: cerebral vasospasm aneurysmal subarachnoid hemorrhage intra arterial drug treatment for cerebral vasospasm nicardipine milrinone nitroglycerin verapamil
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 92
Healthy volunteers: no

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.

Arms:
arm 1: Group 1 : Nicardipine 5mg per circulation intra-arterial injection, Pharmacological angioplasty arm 2: Group 3: Verapamil 10mg per circulation intra-arterial injection, Pharmacological angioplasty arm 3: Group 4 : Nicardipine 5mg + Verapamil 10mg + Nitroglycerin 200mcg in 4cc 5 % dextrose in water , intra-arterial injection, Pharmacological angioplasty

Interventions: intervention 1: Nicardipine intervention 2: Verapamil intervention 3: Nicardipine + Verapamil + Nitroglycerin
Intervention descriptions: intervention 1: Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm intervention 2: Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm intervention 3: Pharmacological angioplasty: intra-arterial drug infusion via catheter to treat cerebral vasospasm

Protocol document:
Prot_SAP_000.pdf: 
14 October 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Intra-arterial Vasospasm Trial - A Multi-center Randomized Study 
 
NCT01996436 
 
Version Date: 11/09/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


14 October 2021 
 
The Intra-arterial Vasospasm Trial 
- A Multicenter Randomized Study 
 
 
 
 
 
Study Chairs: 
Peng Roc Chen, MD 
Study Chair 
Associate Professor of Neurosurgery 
Director Cerebrovascular/Endovascular Program 
Dept. of Neurosurgery 
The University of Texas Health Science Center at Houston 
 
Ketan Bulsara, MD, MBA 
Study Co-Chair 
Professor and Chief, Division of Neurosurgery 
Program Director, Neurosurgery Residency 
Director, Operating Room Quality 
University of Connecticut 
 
Dr. Sunil Sheth, MD 
Steering Committee Member 
Assistant Professor 
Co-Director, Vascular Neurology Fellowship Program 
Department of Neurology 
The University of Texas Health Science Center at Houston 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL 11.0 
 
IRB NUMBER: HSC-MS-13-0586 
IRB APPROVAL DATE: 11/09/2021 


IRB NUMBER: HSC-MS-13-0586 
IRB APPROVAL DATE: 11/09/2021 
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TABLE OF CONTENTS 
Page No 
 
1. SYNOPSIS ................................................................................................................................ 3 
2. STUDY OBJECTIVES… ........................................................................................................ 4 
3. BACKGROUND… ................................................................................................................... 4 
4. STUDY DESIGN… ................................................................................................................... 6 
5. SELECTIONS AND ENROLLMENT OF SUBJECTS ........................................................ 9 
6. STUDY INTERVENTIONS… ............................................................................................. 10 
7. CLINICAL AND LABORATORY EVALUATIONS… .................................................... 11 
8. MANAGEMENT OF ADVERSE EXPERIENCES ........................................................... 13 
9. CRITERIA FOR INTERVENTION DISCONTINUATION ............................................ 13 
10. STATISTICAL CONSIDERATIONS… ........................................................................... 14 
11. DATA COLLECTION, SITE MONITORING AND ADVERSE EVENT 
REPORTING… .......................................................................................................................... 18 
12. HUMAN SUBJECTS… ....................................................................................................... 19 
13. REFERENCES ..................................................................................................................... 20 
 
APPENDICES 
1. List of participating centers 
2. Drug information 
3. Adverse events – definitions, details, monitoring & management plan 
4. Study Flow chart 
5. Drug Dose 
6. Drug Dose Scenario 


IRB NUMBER: HSC-MS-13-0586 
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1. SYNOPSIS 
 
Study Title: The Intra-arterial Vasospasm Trial - A Multicenter Randomized Study 
 
Objectives: The primary objective of the study is to determine the optimal intra-arterial drug 
treatment regimen for arterial lumen restoration after cerebral vasospasm following aneurysmal 
subarachnoid hemorrhage. 
 
The secondary objective is to evaluate clinical outcome 90 days after patient discharge following 
in-hospital optimal intra-arterial drug treatment for cerebral vasospasm. 
 
Design: This study is a prospective multicenter randomized trial. 
 
Outcome variables: 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 Scale (mRS) at 3 months post-hospital discharge will be recorded as a secondary 
outcome to assess overall clinical outcome. 
 
Interventions: The interventions in this study are part of the 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 a single 
drug agent or a cocktail of drug agents will be initiated. 
 
Study participants will be randomly assigned to one of the three treatment groups where one single 
drug agent or a cocktail of drug agents will be intra-arterially administered. Group 1 will be treated 
with nicardipine. Group 2 will be treated with verapamil and Group 3 will be treated with the 
combination of verapamil, nitroglycerin and nicardipine. Pre- and post-infusion vasospasmic vessel 
diameters will be compared. The change in diameter will be quantified based on the mean 
percentage change. At three months post-hospital discharge, study participants will be followed up 
in clinic to evaluate clinical outcomes. 
 
Duration: The total duration for study participation required is the standard hospital stay for post- 
aSAH vasospasm treatment and one follow-up clinic visit at 3 months following hospital discharge. 
 
Sample Size: The study will require a maximum of 330 patients, 110 in each of the three treatment 
regimens. Subjects will be randomized equally into one of three treatment groups. 
 
Population: The patient population will be hospitalized patients presenting with cerebral 
vasospasm post-aneurysmal subarachnoid hemorrhage. 
 
Study time frame: The total study time frame is 24 months (18 months for enrollment + 3 months 
follow up and ± 3 months to accommodate any scheduling conflict and data gathering). 


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2. STUDY OBJECTIVES 
Primary Objective: The primary objective of the study is to determine the optimal intra-arterial 
drug treatment regimen for arterial lumen restoration after cerebral vasospasm following 
aneurysmal subarachnoid hemorrhage. 
We hypothesize that a cocktail of drug agents via infusion will likely improve treatment efficacy 
compared to single agents. 
 
Secondary Objective: The secondary objective is to evaluate clinical outcome 90-days after patient 
discharge following in-hospital optimal intra-arterial drug treatment for cerebral vasospasm 
 
3. BACKGROUND 
Rationale & Supporting Data: 
Cerebral vasospasm is a devastating health problem that is a major contributor to poor outcome 
following subarachnoid hemorrhage (SAH). The estimated case fatality following a SAH is 25-50% 
with a large proportion of these being secondary to the deleterious consequences of delayed 
cerebral vasospasm1, 2. Up to 70% of patients who survive the initial SAH develop signs of 
vasospasm, which, if untreated, can lead to devastating strokes 1,3,4. To this date, the 
armamentarium available for predicting, preventing, and optimizing outcomes following severe 
vasospasm remains limited. 
 
The reason for this poor result is, in part, that the complex pathogenesis of vasospasm has not been 
completely explicated. What is clear though is that between 3 and 21 days after SAH, severe 
vasoconstriction of the intracranial arteries frequently occurs, leading to delayed ischemia and 
commonly devastating strokes. 
 
Despite improved microsurgical and endovascular techniques used to treat aneurysms, we have not 
made significant strides in treating cerebral vasospasm. The traditional therapy acutely using 
hypertensive hypervolemic hemodilution, which has been adopted in clinical practice, presents 
considerable cardiopulmonary risks. Endovascular treatments such as angioplasty and intra-arterial 
drug delivery, particularly of calcium channel blockers, have been considered the quintessential 
treatment for minimizing potential devastating ischemic stroke resulting from delayed cerebral 
vasospasm. 
 
Based on the results of a recent national survey conducted by the two PI’s of this study through the 
joint AANS/CNS cerebrovascular section, there is considerable variability in how intra-arterial of 
cerebral vasospasm is treated. This has led to variable outcomes. 
The commonly used intra-arterial drugs for treating vasospasm are used as single agents, among 
them being verapamil5, nicardipine6, 7 and nitroglycerin. The clinical result is generally considered 
unsatisfactory. There has been no literature that conclusively recommends an optimal intra-arterial 
infusion agent or combination of agents for treating cerebral vasospasm, particularly when balloon 
angioplasty is not feasible for the involved arteries. The end result of treatment is thus generally 
unsatisfactory. 


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A retrospective study8 was recently conducted in consecutive patients treated for cerebral 
vasospasm at The University of Texas Medical School, Memorial Hermann Hospital at the Texas 
Medical Center, a tertiary treatment center in Houston. Two cohorts were involved. Group 1 (N=47 
patients, 116 vessels) was treated between 2008-2011 with a single agent; Group 2 (N=69 patients, 
106 vessels) was treated between 2010-2013 with a cocktail of multiple agents (nitroglycerin, 
verapamil, nicardipine). Patient demographics, age, and modified Rankin score (mRS) at discharge 
and at 3 months were collected in the cerebrovascular database. Arterial luminal diameters were 
measured in cerebral angiograms both pre-infusion (PrID) and post-infusion (PoID). The 
Improvement Ratio (IR) = (PoID - PrID/PrID) x 100 was calculated and statistically compared 
among groups. This study results showed, Group 2 demonstrated a significantly greater 
improvement IR 45.8% (SD 36.6) than Group 1 IR 10.9% (SD 12.0), P<0.001. Multiple agent 
infusion resulted in an average of 34.9% greater vessel diameter improvement than single agent 
therapy. Comparison of the IR between different single agents within Group 1 (nicardipine and 
verapamil) demonstrated no difference in vessel diameter change. Patient age had no effect on 
efficacy in either group. 
The conclusion of this study is that treatment of cerebral vasospasm with an IA cocktail of 
nitroglycerine, verapamil, and nicardipine provides significantly better angiographic improvement 
of vasospasm than does single agent therapy. (This study has been presented at the International 
Stroke Conference 2014, in San Diego, CA). 
 
This encouraging result has led us to pursue this proposed prospective evaluation of the efficacy of 
cocktail drug agent infusion therapy versus the current standard of care single agent therapy that is 
used by the majority of neuro-interventionists throughout the United States. 
 
The goal of this study is to determine the optimal intra-arterial drug treatment regimen for treating 
cerebral vasospasm. 
 
Given that each of currently commonly used intra-arterial vasodilators (verapamil, nitroglycerin and 
nicardipine) has its own mechanisms of action despite some of them belonging to the same drug 
category 9, combining these medications for intra-arterial infusion potentially provides synergistic 
effects of cerebral vasodilation while minimizing cardiovascular instability induced by high doses 
of single agent treatment. 
Based on single center retrospective data from the PI’s center, we hypothesize that infusions of 
cocktail drug agents will improve treatment efficacy compared to single drug agent infusion. 
 
 
Hypothesis: Intra-arterial (IA) infusion of cocktail drug agents is more efficacious than single drug 
agent treatment for cerebral vasospasm therapy. 


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4. STUDY DESIGN 
 
This is a prospective multicenter randomized controlled clinical trial. Endovascular treatment will 
be initiated on hospitalized patients who present with cerebral vasospasm within 3-21 days 
following surgical or endovascular intervention for aneurysmal subarachnoid hemorrhage (aSAH). 
Endovascular treatment will consist of: 
1. Diagnostic angiogram to locate the spasmic blood vessel/vessels. 
 
2. Pharmacological cerebral angioplasty to treat presenting spasm in one or two the following 
arterial vessel territories (if all three territories need treatment: the patient is excluded from 
participation in the study) 
a. Right Carotid Artery Territory: to treat Vasospasm in R Carotid, R ACA, R MCA & its 
branches 
b. Left Carotid Artery Territory: to treat Vasospasm in L Carotid, L ACA, L MCA & its 
branches 
c. Vertebral-Basilar Territory 
 
3. Post-treatment angiogram. 
 
4. Balloon angioplasty may be done if vasodilators fail to produce response or show insufficient 
improvement. 
 
Please refer to Appendix IV Study flow chart for the detailed study design & Flow 
 
Randomization: 
Study participants will be randomly assigned to one of three treatment groups. Randomization will 
be pre-determined and specific to each participating center. At each center only the Research 
Coordinator/Nurse will have access to the randomization pattern. 
Treating physicians will not be blinded by the randomization scheme and will know the drug group 
assigned to the study subject only after the first diagnostic angiogram has been performed, when 
he/she confirms the need for drug treatment. 
However, the subjects enrolled in the trial will be blinded and will not know the treatment group to 
which they have been assigned. 
 
TREATMENT CRITERIA 
 
1. Symptomatic vasospasm - clinical symptoms, with or without Trans-cranial Doppler (TCD) 
study. 
 
2. 50% or more stenosis seen on diagnostic angiogram in asymptomatic patients 


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DRUG DOSE: Patients who qualify for endovascular treatment post aSAH will be randomly 
assigned to one of three treatment groups: 
 
Group 1: Nicardipine (Cardene): 5 mg per circulation in 25 mL 5% Dextrose. 
Infusion rate: 1.25 mL/minute over a period of 20 minutes 
 
Group 2: Verapamil: 10 mg per circulation in 10 ml saline. 
Infusion rate: 1 mL/minute over a period of 10 minutes. 
 
Group 3: 
Verapamil 10 mg in 10 mL saline, Infusion rate: 1 mL/minute over a period of 10 minutes + 
Nitroglycerin (200 mcg in 4 mL 5% dextrose, Infusion rate: 0.5 mL/min over 8 minutes + 
Nicardipine 5 mg in 25 mL 5% Dextrose, Infusion rate 1.25 mL/min over 20 minutes per 
circulation (USE DIFFERENT SYRINGES FOR EACH DRUG. DO NOT MIX DRUGS IN THE 
SAME SYRINGE.) 
 
Perform post-treatment angiogram run minimally 10 minutes after completion of infusion. 
Angiographic Imaging should be recorded 10 minutes after infusion. 
 
ONLY ONE TREATMENT SESSION is permitted per day. 
 
Drug Dosage: Maximum intra-arterial dose allowed within 24-hour period is, nicardipine 10 mg, 
verapamil 20 mg, cocktail (verapamil 20 mg, nitroglycerin 400 mcg & nicardipine 10 mg) 
 
Please refer to Appendix V & VI for detailed drug dosage tabulations. 
 
If the study subject needs another treatment after the first treatment session, use the same drug for 
each repeat treatment. 
Additional doses can be given per the treating physician’s discretion up to the maximum allowed 
dose as per the protocol; please record the additional doses and treatment given in the data 
collection forms. 
Balloon angioplasty can be performed if drug infusions show insufficient improvement per the 
treating physician’s discretion. 
 
A central core laboratory will perform radiographic data assessment and assessors will be blinded to 
treatment group assignment. 
The diameters of the same spasm vessel(s) will be compared before (pre-) and after (post-) infusion 
of the agent/agents, (see figure below). 
 
The diameters will be measured at the following locations: 
ICA supraclinoid segment, MCA M1, MCA M2, ACA A1, ACA A2 & Basilar 
 
The pre-treatment diameter measurement will be at the narrowest spot as is shown in the figure 
below. The post-treatment diameter measurement will be at the same location as the one prior to the 
infusion treatment. 


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Pre-infusion 
Post-infusion 
 
The changes will be quantitated based on the ratio percentage as shown in the following formula. 
 
 
Post-infusion improvement ratio (PIIR) = (B – A)/ A 
 
Example: A = 1 mm 
B = 1.2 mm 
 
PIIR % = (1.2 – 1)/ 1 = 20% 
 
If balloon angioplasty is performed, the artery diameter will still be measured and the measurement 
documented. 
 
Clinical data, that will be collected and entered in REDCap are as follows: 
• Patient demographics (age, gender, BMI, race) 
• Patient medical and surgical history 
• Patient’s current medications 
• The length of time from aneurysm rupture to time of surgical intervention 
• Time in between vasodilator applications 
• Number of drug applications used 
• Dose of drug applications 
• Pre- and post-procedure intracranial pressure measurements (ICPs) 
• Cardiovascular instability (SBP changes in mm Hg, requirement of intravenous [IV] 
pressors) 
• New strokes on CT 
• Modified Rankin Scale, NIHSS (before treatment, at discharge, and at 3 months after 
discharge) 
Patients will have a 3-month follow-up clinic visit as per standard of care after discharge from the 
hospital. A
 B
 


IRB NUMBER: HSC-MS-13-0586 
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5. SELECTION AND ENROLLMENT OF SUBJECTS 
Inclusion Criteria: Only adult patients ≥ 18 years with ruptured aneurysms requiring surgery or 
endovascular therapy and who experience vasospasm post-operatively (3-21 days post-procedure) 
will be enrolled in this study. 
Informed consent will be obtained either from the patient or the patient’s legal representative. 
The institutional PI/Co-PI will determine the eligibility of the patients for the study on the basis of 
the following: 
• Adult patient, age 18 – 80 years old, with ruptured aneurysm(s) who experience vasospasm 
postoperatively 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 patient’s family 
• Pregnant women (confirmed by a positive pregnancy test) 
• Hunt Hess (HH) grade 5 
• Intra-arterial drug treatment in all 3 arterial territories 
 
Study Centers: 
The University of Texas Medical School at Houston 
University of Illinois College of Medicine – Chicago 
Geisinger Health System, 
North Shore University Hospital – Northwell Health 
 
 
 
 
Study Enrollment Procedures: 
Institutional PI & Co-PI will determine a patient’s eligibility based on SOC testing and procedures 
used in treating patients with aneurysms. 
For patients who develop vasospasm during their hospital stay due to aSAH, the PI and members of 
his research team will approach them to request participation in the clinical study. The study 
procedures will be explained to the patient or his/her legal representative in detail and consent 
forms for the study will be explained in detail. Any questions or concerns the participants have will 
be answered in detail, before the patient or his/her representative signs the consent forms and the 
potential participants will be given ample time to make an informed decision. For women who have 
to be excluded from participating in the study on the basis of a suspected pregnancy, a pregnancy 
test needs to be performed to confirm the pregnancy. 
The study coordinator at each site will maintain a log sheets of all the enrolled participants and 
potential participants approached for the study, eligible participants who refuse to participate & 
reasons for nonparticipation. 
The University of Texas Medical School at Houston is the primary center and will maintain records 
from all other participating centers. 


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6. STUDY INTERVENTIONS 
Interventions, Administration, and Study Duration: 
All study interventions done in this trial are standard of care procedures for cerebral vasospasm 
treatment. After obtaining informed consent, a clinical examination will be done to assess patient’s 
neurological status pre-infusion. The patient will be taken to the Interventional Radiology suite 
where he/she will be assigned to one of the three treatment groups based on the center specific 
randomization scheme for endovascular intra-arterial drug infusion. 
Infusions can be given for a total of two times during the same procedure time slot. A post-infusion 
angiogram will be done minimally10 minutes after the treatment to check for improvement in the 
spasmic blood vessel. Balloon angioplasty can be performed if the post-treatment angiogram run 
shows insufficient improvement as per the treating physician’s discretion. Post-infusion clinical 
status will be noted. Three months post-discharge from hospital, study participants will be followed 
up in clinic to evaluate their functional clinical outcome. If, for any reason, the patient cannot come 
back for a follow-up visit, the PI/Co-PI’s will contact the patient via phone/email to gather the 
required data. A minimum of mRS and NIHSS should be gathered for follow-up data. 
 
Handling of Study Interventions: 
Each participating study center will use its available hospital pharmacy services to acquire the drugs 
to be used in the study as per their current standard procedures. The study coordinator at each site 
will maintain a log for study randomization, enrollment and withdrawal. 
Concomitant Interventions: 
Balloon angioplasty can be done if the drugs used fail to improve the spasm in the blood vessels. 
The vessel diameter will still be recorded at the end of the study. 
 
7. CLINICAL AND LABORATORY EVALUATIONS 
 
For this clinical trial no additional clinical or laboratory evaluations are required apart from the 
standard hospital routine care procedures. The required evaluations are listed below: 
Schedule of Evaluations 
 
Table 1. 
Evaluation 
Screening 
Pre- 
Vasospasm 
Treatment 
Post – 
Vasospasm 
Treatment 
3 months 
Follow up 
Informed Consent 
Y 
Pregnancy Test 
Y 
Clinical examination 
mRS, NIHSS, (24-hr window) 
Y 
Y 
Y 
Y 
NON-contrast CT scan (24-hr window) 
Y 
Y 
Y 
Y 
TCD (Lindegaard Index) 
Y 
Y 
Y 
Pharmacological angioplasty 
Intervention 


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Balloon angioplasty 
Concomitant intervention 
Intracranial pressure 
Y 
Y 
Y 
Enter Clinical DATA in REDCAP 
ENTER within 1 week of discharge & F/U 
 
Time Frame: 
Pre-vasospasm treatment: 24 hours prior to procedure 
Post-vasospasm treatment: within 24 hours of the procedure 
3-month follow-up visit: +/- 2 weeks 
Core Lab Image upload: Please upload all angiogram and CT scan images of the patients enrolled 
each month to the core lab website by the 7th calendar day of the preceding month. 


IRB NUMBER: HSC-MS-13-0586 
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Evaluations: 
 
Screening & Pre-entry: Screening & pre-entry evaluations may occur simultaneously. 
Any patient who presents with cerebral vasospasm within 3-21 days after aneurysmal 
SAH and has an intervention done for aneurysm rupture is eligible for this clinical trial 
assuming other inclusion criteria are met. 
 
Entry: On confirming patient eligibility and informed consent process, the patient will be 
randomly assigned to one of the three treatment groups for intra-arterial infusion of study 
drugs. 
On-Study/On-Intervention Evaluations: Pharmacological angioplasty 
Intervention Discontinuation Evaluations: If for any reason the PI or the Co-PI 
discontinue the intervention on a patient, the data will still be collected and entered into 
the data sheet; patients will still receive all medical & surgical care they need as per 
routine hospital care procedures. During analysis data from discontinued participants will 
be factored in. 
 
On Study/Off-Intervention Evaluations: Before discharge from hospital after 
intervention, patient’s neurological status will be noted using Modified Rankin 
scale and NIH Stroke Scale [NIHSS]. Any new changes on CT scan should be 
noted, ICP should be noted, and any procedure complications or delayed procedure 
complications should be noted. 
 
Off-Study Requirements: Study participants will be followed up in clinic at 3 months 
post-discharge from hospital. All participants will receive this follow-up visit, 
even if the study intervention was discontinued. 
 
Informed Consent: Informed consent process will take place in a private room where the 
PI/Co-PI and or the study coordinator will explain the study trial and enrollment process 
to the potential participants. They will be given ample time to understand the study and to 
be asked if they have any questions or concerns. 
 
The Informed Consent form is attached in the appendix below. 
 
Documentation of vasospasm: By clinical symptoms, transcranial doppler ultrasound, 
CT-angiogram & cerebral angiogram. 
 
Clinical Assessments: A complete neurological examination will be done & Modified 
Rankin score (mRS), NIHSS will be noted. At 3-month follow-up appointment, 
there will be a recording taken during the mRS evaluation. This recording will 
contain only the Subject ID and the mRS questions and answers. 


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8. MANAGEMENT OF ADVERSE EVENTS 
This protocol presents minimal risks to the subjects, and adverse events or other problems 
apart from those expected during standard hospital care for this condition are not 
anticipated. 
In the unlikely event that such events occur, serious and unanticipated and related adverse 
events or unanticipated problems involving risks to subjects or others will be reported in 
writing within 48 hours to the institutional review board of the institution involved [IRB], 
using the current procedures followed at each participating center. The primary site 
should also be informed of such an event within 48 hours. All appropriate funding and 
regulatory agencies will be notified there after by the study coordinator 
The investigator will apprise fellow investigators and study personnel of all adverse 
events that occur during the conduct of this research project via email as they are 
reviewed by the principal investigator. The protocol’s research monitor(s), e.g., study 
sponsors, funding and regulatory agencies, and regulatory and decision-making bodies 
will be informed of serious adverse events within 5 days of the event becoming known to 
the principal investigator: 
 
Adverse effects of cerebral angiogram: 
BLEEDING FROM GROIN 
FEMORAL ARTERY OCCLUSION 
STROKE SYMPTOMS (SLURRED SPEECH, WEAKNESS AND/OR LOSS OF 
SENSATION IN FACE, ARMS & LEGS) 
ALLERGIC REACTION TO CONTRAST AGENT 
KIDNEY DAMAGE 
SEVERE HEADACHE 
 
Details of adverse events, management & monitoring plan for adverse events is listed in 
appendices 
 
9. CRITERIA FOR INTERVENTION DISCONTINUATION 
 
The PI & Co-PI can discontinue study intervention(s) based on their clinical judgment 
& patient’s best interest. All the data that needs to be entered in the Case Report Form 
(CRF) will be collected and data from discontinued study participants will be factored 
in in the analysis. 


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10. STATISTICAL CONSIDERATIONS 
 
Design: 
The clinical trial will be conducted under a common umbrella protocol developed by the 
primary site (UTH) with the intention of combining data from all satellite centers for 
analysis. Each investigational site will give utmost importance to follow the study 
protocol to maintain consistency in study execution at all centers. Patients will be 
randomly assigned to 3 treatment groups in a 1:1:1 allocation ratio. The three therapeutic 
regimens to be considered are: 
Group 1: nicardipine (Cardene) 5 mg per circulation in 25 mL of 5% Dextrose, 
Group 2: verapamil 10 mg per circulation in 10 mL saline 
Group 3: Cocktail agents: 5 mg in 25 mL 5% Dextrose + verapamil 10 mg in 10 mL 
saline + nitroglycerin 200 mcg in 4 cc of D5W per circulation. 
 
A maximum of 330 subjects, 110 per treatment arm, will be randomized. The trial 
includes interim analyses that may reduce the maximal sample size if clear differences 
emerge among the arms during the conduct of the trial. 
 
Interim Analyses: 
Interim analyses will be performed to allow for discontinuing enrollment to treatment 
arms due to futility. After approximately 90 subjects have been randomized, 30 per arm, 
interim analyses will begin at the next quarterly Data and Safety Monitoring Board 
(DSMB) meeting. Subsequent interim analyses will be performed to coincide with 
DSMB meetings, which will occur after 40 subjects, 70 subjects, 110 subjects, 165 
subjects, and 248 subjects have completed the study, and at the conclusion of the study 
(330 subjects). 
 
At each interim analysis, an Analysis of Variance (ANOVA) will be performed to 
compare the PIIR results across treatment arms. If the overall treatment effect is 
significant with a p-value<0.05, then pairwise treatment comparisons will be performed. 
If any pairwise comparison is significant at a Tukey’s adjusted two-sided p-value of 0.02 
(p< 0.02), the poor performing arm will be dropped from the randomization scheme. If 
multiple arms are dropped and only one treatment arm remains open for randomization, 
that arm will be declared as best, and the clinical trial will end. Pairwise comparisons 
will only be performed if the overall treatment effect in the ANOVA is significant. 
 
A maximum of 110 subjects will be randomized to each treatment arm, for a total sample 
size of 330. If an arm or arms are dropped early, the final sample size will be less than 
330. For example, suppose an interim analysis is performed after 70 subjects are 
randomized to the 3 treatment arms (total sample size 210). Suppose further, at the 
interim analysis one arm is dropped, and the remaining two arms continue to enroll to 
completion. The final sample size will be 290, i.e., 70 subjects in the dropped treatment 
arm, and 110 in each of the remaining treatment arms. 
 
Enrollment will continue while the interim analyses are performed 


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Final Analyses: 
All patients will be included in analyses utilizing the Intent-to-Treat approach that 
includes all subjects randomized in their randomized treatment arm regardless of 
treatment received. 
 
At the final analysis, the primary outcome measure, PIIR will be compared between 
treatment arms using an ANOVA model. All data will be used in the final analysis, 
including any arms that may have been dropped from the randomization. If the overall 
treatment effect in the ANOVA model is significant at the two-sided, 5% level, then 
pairwise comparisons among treatment arms will be conducted using Tukey’s adjusted p- 
values with p<0.0330 declared as statistically significant. This value controls global type 
I error (mistakenly claiming any pairwise difference when all treatments are equal) 
accounting for 6 interim analyses at the anticipated accrual rate of 2 years. If accrual 
significantly deviates from the anticipated accrual rate, further trial simulations will be 
conducted to determine an appropriate adjustment for the actual number of interim 
analyses conducted. 
 
Descriptive statistics, means, medians, and standard deviations, will be reported for PIIR 
in each treatment arm. The two-sided 95% confidence interval will also be presented for 
the PIIR in each treatment arm. 
 
The key secondary outcome, mRS (Modified Rankin Scale) at 3-months post-treatment, 
will be summarized by treatment arm by reporting the counts and proportions in each 
mRS category. Comparisons among treatment groups will be made using a Chi-square 
test. 
 
Additional secondary outcomes include SAE (severe adverse event) occurrences and the 
rate of treatment failure with balloon angioplasty. These outcomes will be summarized 
descriptively by presenting rates and proportions. Exploratory analyses comparing 
outcomes between treatment arms will be made using a Chi-square test. 
 
Additional exploratory multivariable linear regression models will be created for the PIIR 
outcome, adjusting for treatment groups and additional baseline factors. 
 
The analyses for the secondary outcomes are considered exploratory and no adjustments 
for the multiple tests and multiple comparisons will be made. Results will be interpreted 
cautiously understanding the some results may be significant at the 5% level due to 
chance alone. 
 
Sample Size Justification: 
Simulations were performed to estimate the power of the study for the primary outcome 
measure, PIIR, with a maximum sample size of 330 (110 per treatment arm) and the 
interim analyses for possible early arm dropping. A range of scenarios of PIIR were 
examined; the key scenarios used to power the trial are presented in Table 2. 


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Table 2. 
Scenario 
Treatment Arm 1: 
Nicardipine (N) 
Treatment Arm 2: 
Verapamil (V) 
Treatment Arm 3: 
Combination (C) 
Combo 20 
0.10 
0.10 
0.30 
Mixed 1530 
0.10 
0.15 
0.30 
 
Note that the scenarios are both in favor of Verapamil over Nicardipine, but the results 
are symmetric if Nicardipine and Verapamil were reversed. 
 
The trial will make every pairwise comparison: 
• N versus V 
• N versus C 
• V versus C 
 
The simulations focused on the V>N, C>N, and C>V comparisons. The following table 
presents the expected (mean) sample size and probability that the combination treatment 
regimen is better than the verapamil regimen, i.e., Pr(C>V), the main comparison of 
interest. Power is defined as the probability of identifying the superiority of the best dose 
over the other two doses. 
 
Table 3. 
Scenario 
Expected N 
Power 
Pr(C>V) 
Combo 20 
177 
0.95 
Mixed 1530 
211 
0.77 
 
Table 3 demonstrates, that for a hypothesized scenario of “Combo 20” where the 
combination therapy PIIR is 0.30 compared to 0.10 in Nicardipine and Verapamil, the 
study will have over 90% power and an expected sample size of 177. Both the 
Nicardipine and Verapamil arms would have been dropped at interim analyses before 
they reached their maximum enrollment of 110. If the scenario of “Mixed 1530” is 
observed, a situation where the Nicardipine arm PIIR is 0.10, the Verapamil arm PIIR is 
0.15 and the combination arm is 0.30, the study will have 77% power and an expected 
sample size of 211. Again, both the Nicardipine and Verapamil arms would have been 
dropped at interim analyses before they reached their maximum enrollment of 110. 
 
Missing Data and Dropout Rate: We do not anticipate missing data for the primary 
outcome PIIR as the angiogram will be performed 10 minutes post-infusion. For the 
secondary outcome, mRS at 3-months, based on previous studies, we estimate up to a 
20% loss follow-up. Efforts will be made to keep all patients in the study through the 3- 
month follow-up visit. Substantial efforts will be made to ensure complete follow-up. 
Rates of missing data and loss to follow-up will be reported by treatment arm. We will 
attempt to document maximum amount of information regarding the status of these 


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patients who drop out. This procedure will help to compare characteristics of those 
patients who completed the study with those who did not. 
 
Data and Safety Monitoring: 
In order to ensure patient safety and integrity of data collection, data and safety 
monitoring during this trial will include both internal and external mechanisms. The PI 
has developed an internal monitoring system, which will be implemented after each 
enrolled patient and on a monthly basis at the host site, University of Texas Health 
Science Center Houston. The study team will perform internal monitoring. In addition, on 
a yearly basis, a monitor will be asked to review study and safety data for all participating 
centers. Monitoring of participating centers will occur on a yearly basis, or following the 
completion of the study for each additional two subjects at each center, whichever occurs 
first. Monitoring may occur in person, or remote. Lastly, the Data and Safety Monitoring 
Board will independently review the accumulating data, assess the risk to benefit ratio, 
and can consider halting the trial if the risk to benefit ratio is deemed unacceptable. The 
external monitor and the DSMB will also monitor protocol compliance, safety, and on- 
schedule study progress. 


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11. DATA COLLECTION, SITE MONITORING AND ADVERSE EVENT 
REPORTING 
 
Data collection: detailed clinical information will be gathered using an established 
method approved by UT Health for abstracting information from electronic database and 
by the approved established method at each participating site. 
Each participating center will use REDCap data software an online secure web 
application to enter the data in the central REDCap database managed by UT-Houston. 
All the radiographic images will be evaluated and analyzed by a single CORE LAB (at The 
University of California – Los Angeles) centrally in blind fashion. The radiographic images 
will be submitted via VPN with security and with federal Health Insurance Portability and 
Accountability Act (HIPPA) compliance. 
 
The patient’s demographics (gender, age, race, BMI, co-morbidity, tobacco use, 
cocaine/illicit drug use history), aneurysm treatment modality, days after the SAH and 
aneurysm treatment, vasodilator(s) used (Group #) and numbers of the treatment sessions 
will be submitted via REDCap. Summaries will be provided quarterly to the DSMB 
members. 
 
Records to Be Kept: All patient data will be de-identified and CRFs will be stored on 
password protected cloud drive 
 
Data and Safety Monitoring Plan & Quality Assurance: 
The Data and Safety Monitoring Board (DSMB) is responsible for conducting on going 
safety reviews of the trial. The first meeting will be held when approximately 40 subjects 
have completed the study and subsequent meetings will be held at following each of the 
following study timepoints, or every 6 months, whichever occurs first. 
 
• 70 subjects completed the study 
• 110 subjects completed the study 
• 165 subjects completed the study 
• 248 subjects completed the study 
• 330 subjects completed the study 
 
(Subject completion of the study will be defined as a subject having a completed 90-day 
follow up and completed analysis of study imaging by the corelab) 
 
Frequency of the meetings may be changed by the Chair based on need. Meetings may 
be in person, via teleconference, or a combination of the two. A quorum must occur for 
the meeting to proceed. 
 
During the review process the DSMB will evaluate whether the study should continue 
unchanged, require modification/amendment or be closed to enrollment and will inform 
the trial co-PIs of the study. 
The trial co-PIs are responsible for communicating with DSMB at each time point listed 
above regarding potential safety issues and whether the study should continue unchanged, 


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require modification/amendment, or be closed to enrollment. These will be further 
communicated with the individual participating local PIs. 
 
The principal investigator or the Institutional Review Board (IRB) have the authority to 
stop or suspend the study or require modifications. 
 
Data Safety Monitoring Board 
Dr. David Langer; 
Dr. Kevin Cockroft. 
Dr. Juliana Tolles 


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12. HUMAN SUBJECTS 
Institutional Review Board (IRB) Review and Informed Consent: 
This protocol, the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for oversight of the 
study.  A signed consent form will be obtained from the subject.   For subjects who 
cannot consent for themselves, such as those below the legal age, a parent, legal guardian, 
or person with power of attorney, must sign the consent form; additionally, the subject's 
assent must also be obtained if he or she is able to understand the nature, significance, 
and risks associated with the study. The consent form will describe the purpose of the 
study, the procedures to be followed, and the risks and benefits of participation. A copy 
of the consent form will be given to the subject, parent, or legal guardian, and this fact 
will be documented in the subject’s record. 
 
Subject Confidentiality: 
All records that leave any study site will be identified only by the Study Identification 
Number (SID) to maintain subject confidentiality.  All records will be kept in a locked 
file cabinet. All computer entry and networking programs will be done using SIDs only. 
Clinical information will not be released without written permission of the subject, except 
as necessary for monitoring by IRB, the FDA, the NINDS, the OHRP, the sponsor, or the 
sponsor’s designee. All data will be digitally stored on a UT Z100 password protected 
cloud drive. 
 
Study Modification/Discontinuation: 
The study may be modified or discontinued at any time by the PI, IRB, the NINDS, the 
OHRP, the FDA, or other government agencies as part of their duties to ensure that 
research subjects are protected. 


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13.  REFERENCES 
 
1. Dorsch, N. W. & King, M. T. A review of cerebral vasospasm in aneurysmal 
subarachnoid haemorrhage Part I: Incidence and effects. J Clin Neurosci 1, 19-26 
(1994). 
2. Treggiari, M. M., Walder, B., Suter, P. M. & Romand, J. A. Systematic review of 
the prevention of delayed ischemic neurological deficits with hypertension, 
hypervolemia, and hemodilution therapy following subarachnoid hemorrhage. J 
Neurosurg 98, 978-984 (2003). 
3. Biller, J., Godersky, J. C. & Adams, H. P. J. Management of aneurysmal 
subarachnoid hemorrhage. Stroke 19, 1300-1305 (1988). 
4. Kassell, N. F., Sasaki, T., Colohan, A. R. & Nazar, G. Cerebral vasospasm 
following aneurysmal subarachnoid hemorrhage. Stroke 16, 562-572 (1985). 
5. Keuskamp, J., Murali, R. & Chao, K. H. High-dose intraarterial verapamil in the 
treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J 
Neurosurg 108, 458-463 (2008). 
6. Linfante, I., et al. Angiographic and hemodynamic effect of high concentration of 
intra-arterial nicardipine in cerebral vasospasm. Neurosurgery 63, 1080-6; 
discussion 1086 (2008). 
7. Badjatia, N. et al. Preliminary experience with intra-arterial nicardipine as a 
treatment for cerebral vasospasm. AJNR Am J Neuroradiol 25, 819-826 (2004). 
8. Chen, P.R. et al. Use of single versus multiple vasodilator agents in the treatment 
of cerebral vasospasm: is more better than less? Acta Neurochirurgica 163, 161- 
168 (2021). 
9. Pierot, L., Aggour, M. & Moret, J. Vasospasm after aneurysmal subarachnoid 
hemorrhage: recent advances in endovascular management. Curr Opin Crit Care 
16, 110-116 (2010). 
10. Oates, j. et al. Antihypertensive agents and the drug therapy of hypertension. 
(McGraw- Hill, New York, 2001). 
11. Fraticelli, A. T., Cholley, B. P., Losser, M. R., Saint Maurice, J. P. & Payen, D. 
Milrinone for the treatment of cerebral vasospasm after aneurysmal subarachnoid 
hemorrhage. Stroke 39, 893-898 (2008). 
12. Berry, Donald A. "Bayesian clinical trials." Nature Reviews Drug Discovery 5, 
no. 1 (2006): 27-36. 
13. Spiegelhalter, David J., Jonathan P. Myles, David R. Jones, and Keith R. Abrams. 
"Methods in health service research: an introduction to bayesian methods in 
health technology assessment." BMJ: British Medical Journal 319, no. 7208 
(1999): 508 
14. Lilford, Richard J., J. G. Thornton, and D. Braunholtz. "Clinical trials and rare 
diseases: a way out of a conundrum." Bmj 311, no. 7020 (1995): 1621-1625. 
15. McCullagh, Peter. "Generalized linear models." European Journal of Operational 
Research 16, no. 3 (1984): 285-292. 


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APPENDIX 
 
I. List of Participating Centers: 
 
1. The University of Texas Medical School at Houston 
2. University of Illinois in Chicago 
3. Geisinger Health System 
4. North Shore University Hospital – Northwell Health 
5. Memorial Hermann Hospital- At The Woodlands 
 
 
II. Drug Information: The dose of the each medication set in this study is based on the 
limited clinical data available for each agent. 
1) Nicardipine: a dihydrophyridine calcium channel blocker, the therapeutic effect is 
believed to be related to the selective inhibition of transmembrane calcium ion influx into 
vascular smooth muscle, resulting in a reduction of free calcium ions in these cells and 
disruption of actin-myosin interaction essential to muscle contraction 9. The dose used 
frequently in IA therapy is ranges 2 – 25 mg/each arterial territory, mean dose 5.7 +/- 4.3 
mg 6. High dose IA nicardipine results hypotension, in some cases, even dose ranging 
from 4 to 7.5mg. 
2) Verapamil: a phenylalkylamin calcium channel blocker that inhibits voltage-gated 
calcium channels in the arterial wall smooth muscle cells and results in vasodilation. It 
has been observed that there were no significant changes in BP, HR or ICP after 
administration of more than 20mg of IA verapamil 5. 
3) Nitroglycerin: has been used in cerebral vasospasm treatment for a couple of decades. 
It has been reported dose of single vascular territory used up to 700 mcg without major 
hemodynamic instability. 


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III. Adverse events: 
 
 
Term 
Definition 
 
Adverse Event 
(AE) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the 
investigational drugs. 
 
NOTE 1 This definition includes events related to the investigational 
drugs. 
NOTE 2 This definition includes events related to the procedures involved. 
 
Adverse drug 
effect 
Serious adverse 
event 
Any AE related to the use of an investigational drug. 
 
Any AE that 
a) led to death, 
b) led to serious deterioration in the health of the subject that either 
resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure 
required by this Protocol, without serious deterioration in health, is not 
considered a serious adverse event. (ISO 14155, 2011) 
 
Technical Event 
A study procedure related event. 
 
Stroke 
New Stroke event, worsening of motor, sensory or speech function. Cant 
be explained by cerebral vasospasm and or pre-existing aSAH Clinically 
and radiographically. 
 
Neurologic Death 
For the purposes of study endpoints, neurologic death is defined as any 
death determined to be of neurologic cause. This definition excludes: 
death due to rupture of a nonindex aneurysm or as a consequence of 
treatment of a nonindex aneurysm. 
 
Death 
For the purposes of study endpoints, death excludes death of accidental 
causes or death due to rupture of a nonindex aneurysm or as a consequence 
of treatment of a nonindex aneurysm. 
 
 
Study procedure related Minor complications might include: 


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Nausea and/or vomiting (post-anesthesia) 
Mild headache 
Groin discomfort: mild pain and or bruising at the incision site 
 
 
Study Procedure related Significant complications (catheter induced: different from pre- 
existing cerebral vasospasm & SAH induced ischemia): 
Intra-cranial catheter induced spasm of the treated segment of artery or branches 
Stroke (ischemic, hemorrhagic, TIA) 
Hemiplegia 
Aphasia 
Visual impairment or blindness 
Intra cranial artery tear (hemorrhage) 
Femoral artery occlusion due to catheter 
 
 
Study Procedure related Very Rare side effects may include: 
Death 
Renal failure due to dye induced 
Seizure 
Infection 
Blood vessel or nerve damage 
Decreased blood flow in the leg on the side of the groin puncture 
A pseudoaneurysm may develop as a result of injury to all the layers of a vessel wall 
resulting in a hematoma 
Air embolism 
Mental status changes 
Total occlusion of the treated blood vessel segment or other blood vessels. 


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DRUG RELATED adverse events & overdose effects: 
NOTE: All drug related adverse events & overdose effects listed below are excerpts from 
the package inserts. The package inserts used as a reference are for IV doses since no 
data is available on Intra-arterial package inserts 
 
1. NICARDIPINE 
 
ADVERSE EVENTS: 
Body as a Whole: headache, fever, neck pain 
Cardiovascular: hypertension, tachycardia, angina pectoris, atrioventricular block, ST 
segment depression, inverted T wave, deep vein thrombophlebitis 
Digestive: nausea, vomiting, dyspepsia 
Hemic and Lymphatic: thrombocytopenia 
Metabolic and Nutritional: hypophosphatemia, peripheral edema 
Nervous: confusion, hypertonia 
Respiratory: respiratory disorder 
Special Senses: conjunctivitis, ear disorder, tinnitus 
Urogenital: urinary frequency 
Sinus node dysfunction and myocardial infarction, which may be due to disease 
progression, have been seen in patients on chronic therapy with orally administered 
nicardipine. 
 
OVERDOSAGE: 
Several overdosages with orally administered nicardipine have been reported, IA 
overdoses are not known as yet. 
One adult patient allegedly ingested 600 mg of nicardipine [standard (immediate-release) 
capsules], and another patient, 2160 mg of the sustained-release formulation of 
nicardipine. 
Symptoms included marked hypotension, bradycardia, palpitations, flushing, drowsiness, 
confusion and slurred speech. All symptoms resolved without sequelae. 
An over dosage occurred in a one-year-old child who ingested half of the powder in a 30 
mg nicardipine standard capsule. The child remained asymptomatic. 
Based on results obtained in laboratory animals, lethal overdose may cause systemic 
hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular 
conduction block. 
Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted 
in some animal species receiving very large doses of nicardipine. 
For treatment of overdosage, implement standard measures including monitoring of 
cardiac and respiratory functions. Position the patient so as to avoid cerebral anoxia. Use 
vasopressors for patients exhibiting profound hypotension. 
 
 
2. VERAPAMIL 
 
ADVERSE EVENTS: 
The following reactions were reported with verapamil hydrochloride injection used in 


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controlled U.S. clinical trials involving 324 patients: 
Cardiovascular: Symptomatic hypotension (1.5%); bradycardia (1.2%); severe 
tachycardia (1.0%). 
The worldwide experience in open clinical trials in more than 7,900 patients was similar. 
Central Nervous System Effects: Dizziness (1.2%); headache (1.2%). Occasional cases of 
seizures during verapamil injection have been reported. 
Gastrointestinal: Nausea (0.9%); abdominal discomfort (0.6%). 
In rare cases of hypersensitive patients, broncho/laryngeal spasm accompanied by itch 
and urticarial has been reported. 
The following reactions have been reported at low frequency: emotional depression, 
rotary nystagmus, sleepiness, vertigo, muscle fatigue, diaphoresis, and respiratory failure. 
 
OVERDOSAGE 
Treatment of over dosage should be supportive and individualized. Beta-adrenergic 
stimulation and/or parenteral administration of calcium injections may increase calcium 
ion flux across the slow channel, and have been effectively used in treatment of 
deliberate over dosage with oral verapamil hydrochloride. 
Verapamil cannot be removed by hemodialysis. 
Clinically significant hypotensive reactions or high-degree AV block should be treated 
with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by 
the usual measures including isoproterenol hydrochloride, other vasopressor agents, or 
cardiopulmonary resuscitation. 
 
 
3. NITROGLYCERIN 
 
Adverse reactions to nitroglycerin are generally dose-related and almost all of these 
reactions are the result of nitroglycerin's activity as a vasodilator. Headache, which may 
be severe, is the most commonly reported side effect. Headache may be recurrent with 
each daily dose, especially at higher doses. Transient episodes of lightheadedness, 
occasionally related to blood pressure changes, may also occur. Hypotension occurs 
infrequently, but in some patients it may be severe enough to warrant discontinuation of 
therapy. 
Syncope, crescendo angina, and rebound hypertension have been reported but are 
uncommon. 
Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in 
normal seeming patients. Methemoglobinemia is so infrequent at these doses that further 
discussion of its diagnosis and treatment is deferred. 
 
 
 
OVERDOSE: 
The ill effects of nitroglycerin overdose are generally the results of Nitroglycerin’s 
capacity to induce vasodilatation, venous pooling, reduced cardiac output, and 
hypotension. 


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No specific antagonist to the vasodilator effects of nitroglycerin is known, and no 
intervention has been subject to controlled study as a therapy of nitroglycerin overdose. 
Because the hypotension associated with nitroglycerin overdose is the result of 
venodilatation and arterial hypovolemia, prudent therapy in this situation should be 
directed toward increase in central fluid volume. Passive elevation of the patient's legs 
may be sufficient, but intravenous infusion of normal saline or similar fluid may also be 
necessary. 
Methemoglobinemia- The diagnosis should be suspected in patients who exhibit signs of 
impaired oxygen delivery despite adequate cardiac output and adequate arterial pO. 
Classically, methemoglobinemic blood is described as chocolate brown, without color 
change on exposure to air. 
When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1-2 
mg/kg intravenously 


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Monitoring Plan: 
During the Intra-Arterial Drug infusion Treatment all patients will be under General 
Anesthesia (GA). Neuro- Anesthetist will manage & monitor these patients during the 
treatment procedure, pre & post procedure they will be closely monitored & managed in 
Neurological Intensive Care unit (ICU) by ICU team. 
Data will be collected at 12-hour intervals pre & post procedure. 
Intra procedure data to be collected is Vital signs (Blood Pressure, Heart Rate), ECG, 
arterial pressure, Intra-cranial Pressure. 
If any drug related complications occur the medications will be stopped immediately. 
The following conditions would warrant for immediate stopping of the study drug: 
Marked hypotension, bradycardia, severe tachycardia, high degree AV-block, asystole, 
crescendo angina & methemoglobinemia 
 
A protocol deviation is defined as any study action taken by the investigator or site 
personnel in conflict with the study protocol. The investigator and/or sponsor will 
characterize deviation severity as per the following Table. 
 
 
Deviation severity 
Definition 
Major deviation: 
Any deviation from subject inclusion and 
exclusion criteria, subject informed consent 
procedures or unauthorized drug use. 
Minor deviation: 
Deviation from a protocol requirement such 
as incomplete/inadequate subject testing 
procedures, follow-ups performed outside 
specified time windows, etc. 
 
Investigators must notify the Study Chairs & respective IRB within 24 hours if a 
deviation is required to protect subject safety. The Study Chairs may terminate 
investigators and/or investigative sites from the study if the rate of protocol deviations is 
deemed high or patient safety is in question. 
 
During the DSMB reviews, occurring every 6 months at a minimum, the DSMB 
members will review all serious related AE’s (catheter induced spasm, new ischemic 
stroke, hemiplegia, aphasia, visual impairment or blindness, Intra cranial artery tear) to 
adjudicate if the SAE’s are procedure related, drug related or other. The DSMB members 
may terminate investigators and/or investigative sites from the study if the rate of 
protocol deviations is deemed high or patient safety is in question. 


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IV. STUDY FLOW CHART 
 
 


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V. DRUG DOSE TABULATION 
 
NICARDIPINE 
Drug Label suggested 
dose 
Maximum dose of 15 mg/hour (0.25 mg/minute) 
Until desired blood pressure reduction is achieved. 
Reference: page 6 of 
package insert 
Drug Label suggested 
infusion rate 
75 mL/hour (1.25 mL/minute) 
Concentration: 0.2 mg/mL 
Reference: page 7 of 
package insert 
Revised drug dose per 
infusion 
5 mg in 25 mL 5% Dextrose 
Infused at the rate of 1.25 mL/ minute (i.e. 0.25 mg/minute) over a period of 
20 minutes 
 
 
VERAPAMIL 
Drug Label suggested 
dose 
Initial dose: 5-10mg/2minutes (2.5-5 mg/minute) 
Repeat dose: 10mg, 30 minutes after the first dose if 
initial response not adequate. 
Reference: page 7 of 
package insert 
Drug Label suggested 
infusion rate 
2.5 – 5mg/minute 
Concentration: 2.5 mg/mL 
Reference: page 8 of 
package insert 
Drug dose 
10 mg in 10 mL normal saline 
Infused at the rate of 1 mL/minute (i.e. 1 mg/minute) over a period of 10 
minutes 
 
 
NITROGLYCERIN 
Drug Label suggested 
dose 
25 mcg/minute or more 
Reference: page 6 of 
package insert 
Drug Label suggested 
infusion rate 
0.5 ml/minute 
Concentration: 50 mcg/mL 
Reference: page 7 of 
package insert 
Revised drug dose per 
infusion 
200 mcg in 4 mL 5% dextrose 
Infused at the rate of 0.5 mL/minute (i.e. 25mcg/minute) over a period of 8 
minutes 


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VI. MAXIMUM POSSIBLE DRUG DOSES: 
 
NICARDIPINE (Arm 1) DRUG DOSE SCENARIOS 
Treatment Session 1 
Treatment Session 2 
(24-48 hours after 
treatment session 1) 
Treatment Session 3 
(24-48 hours after 
treatment session 2) 
All 3 
Treatment 
Sessions 
No of arterial 
territory to be 
infused 
Infusion 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour 
period 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour 
period 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour 
period 
Total 
maximum 
dose for all 
treatments 
One Arterial 
territory 
Infusion 1 
5 mg 
10 mg 
5 mg 
10 mg 
5 mg 
10 mg 
30 mg 
Repeat infusion 
5 mg 
5 mg 
5 mg 
Two Arterial 
territories 
Infusion in First 
arterial territory 
5 mg 
10 mg 
5 mg 
10 mg 
5 mg 
10 mg 
30 mg 
Infusion in 
Second arterial 
territory 
5 mg 
5 mg 
5 mg 
 
VERAPAMIL (Arm 2) DRUG DOSE SCENARIOS 
Treatment Session 1 
Treatment Session 2 
(24-48 hours after 
treatment session 1) 
Treatment Session 3 
(24-48 hours after 
treatment session 2) 
All 3 
Treatment 
Sessions 
No of arterial 
territory to be 
infused 
Infusion 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour period 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour period 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour period 
Total 
maximum 
dose for all 
treatments 
One Arterial 
territory 
Infusion 1 
10 mg 
20 mg 
10 mg 
20 mg 
10 mg 
20 mg 
60 mg 
Repeat infusion 
10 mg 
10 mg 
10 mg 
Two Arterial 
territories 
Infusion in First 
arterial territory 
10 mg 
20 mg 
10 mg 
20 mg 
10 mg 
20 mg 
60 mg 
Infusion in 
Second arterial 
territory 
10 mg 
10 mg 
10 mg 
 
COCKTAIL DRUG (Arm 3) DOSE SCENARIOS (per each infusion: VERAPAMIL 10 mg + NITROGLYCERIN 200 
mcg + CARDENE 5 mg) 
Treatment Session 1 
Treatment Session 2 
(24-48 hours after 
treatment session 1) 
Treatment Session 3 
(24-48 hours after 
treatment session 2) 
All 3 
Treatment 
Sessions 
No of Arterial 
territory to be 
infused 
Infusion 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour 
period 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour 
period 
Drug 
Infusion 
Dose 
Total 
maximum 
dose in 24 
hour 
period 
Total 
maximum 
dose for all 
treatments 
One Arterial 
territory 
Infusion 1 
10 mg + 
200 mcg 
+ 5 mg 
20 mg + 
400 mcg + 
10 mg 
10 mg + 
200 mcg 
+ 5 mg 
20 mg + 
400 mcg + 
10 mg 
10 mg + 
200 mcg 
+ 5 mg 
20 mg + 
400 mcg + 
10 mg 
60 mg + 
1200 mcg + 
30 mg 
Repeat infusion 
10 mg + 
200 mcg 
+ 5 mg 
10 mg + 
200 mcg 
+ 5 mg 
10 mg + 
200 mcg 
+ 5 mg 
Two Arterial 
territories 
Infusion in First 
arterial territory 
10 mg + 
200 mcg 
+ 5 mg 
20 mg + 
400 mcg + 
10 mg 
10 mg + 
200 mcg 
+ 5 mg 
20 mg + 
400 mcg + 
10 mg 
10 mg + 
200 mcg 
+ 5 mg 
20 mg + 
400 mcg + 
10 mg 
60 mg + 
1200 mcg + 
30 mg 
Infusion in 
Second arterial 
territory 
10 mg + 
200 mcg 
+ 5 mg 
10 mg + 
200 mcg 
+ 5 mg 
10 mg + 
200 mcg 
+ 5 mg 


IRB NUMBER: HSC-MS-13-0586 
IRB APPROVAL DATE: 11/09/2021 
32 
 
 
 
Contacts: 
Dr. P Roc Chen, MD 
Study Chair 
Associate Professor, Director Cerebrovascular/Endovascular Program 
Dept. of Neurosurgery 
The University of Texas Health Science Center at Houston 
Peng.R.Chen@uth.tmc.edu 
 
Dr. Ketan Bulsara, MD 
Study Co-Chair 
Professor and Chief, Division of Neurosurgery 
Program Director, Neurosurgery Residency 
Director, Operating Room Quality 
University of Connecticut 
 
 
Dr. Sunil Sheth, MD 
Steering Committee Member 
Assistant Professor 
Co-Director, Vascular Neurology Fellowship Program 
Department of Neurology 
The University of Texas Health Science Center at Houston 
 
Mr. Eddie Aguilar, BA 
Study Coordinator 
Dept. of Neurosurgery UT Medical School at Houston 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
Eddie.Aguilar@uth.tmc.edu 
 
Clinical Trial No: NCT01996436 
UTHSC Protocol No: HSC-MS- 13-0586 
 
IND No: 127428