Clinical trial NCT03000283
Conditions: Cerebral Hemorrhage Cerebral Edema Intracerebral Hemorrhage Stroke
Keywords: Conivaptan
Sponsor: Jesse Corry
Start date: 2017-03-22; Completion date: 2019-04-15
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this study is to preliminarily determine/estimate feasibility and whether frequent and early conivaptan use, at a dose currently determined to be safe (i.e., 40mg/day), is safe and well-tolerated in patients with cerebral edema from intracerebral hemorrhage (ICH) and pressure (ICP). A further goal is to preliminarily estimate whether conivaptan at this same dose can reduce cerebral edema (CE) in these same patients. This study is also an essential first step in understanding the role of conivaptan in CE management.

Hypothesis: The frequent and early use of conivaptan at 40mg/day will be safe and well-tolerated, and also reduce cerebral edema, in patients with intracerebral hemorrhage and pressure.

Detailed description:
This is a single-center, open-label, safety and tolerability study. Based on findings in the literature from both animal research and clinical observations with ICH (intracerebral hemorrhage) associated with TBI (traumatic brain injury), this study will begin to look at the safety, tolerability, as well as potential effectiveness, of conivaptan to reduce CE (cerebral edema) in patients with non-traumatic ICH.

The seven patients in this study will receive 40mg/day of the study medication conivaptan. In this early phase study, our focus will be to assess the safety and tolerability of this medication. The available clinical data on conivaptan in the neurocritical care population suggest the potential harm is negligible. Data in TBI patients demonstrate conivaptan is safe and well tolerated using a single dose (20mg) to increase Na+ in a controlled fashion to reduce ICP. Previous work has demonstrated the safety and tolerability of conivaptan, in doses ranging from 20-80mg/day, in the neurocritical care population. Conivaptan has been demonstrated to be safe and effective in lowering ICP, and increasing serum sodium, in the neurocritical care population. Also noted have been improvements in cerebral perfusion pressure (CPP) and stable blood pressure, and a prolonged reduction in ICP. Finally, the method of intermittent bolus dosing of conivaptan is equally effective in raising and maintaining serum sodium in the neurocritical care population as continuous infusion, with potentially less risk of adverse reactions including phlebitis.

Conivaptan, a non-selective Arginine-Vasopressin (AVP) V1A/V2 antagonist that reduces aquaporin 4 production and promotes aquaresis, is approved for the treatment of euvolemic and hypervolemic hyponatremia. The exact cause of the observed reduction in ICP with conivaptan is uncertain. However, the mechanism most likely represents a combination of an acute pure aquaresis, removing free water from brain tissue, and a sustained down regulation of aquaporin 4 to abate/slow development of CE. The V2 antagonism of conivaptan promotes free water loss, and the V1 antagonism may improve cerebral blood flow (CBF) and reduce blood brain barrier permeability. Notably, serum sodium tends to correlate inversely with both ICP and CE. The early use of conivaptan could potentially be used clinically to reduce CE by these means.

It is with this in mind, the research team feels justified in pursuing this study with the hopes that the data obtained will lead to potential good and removal of harm in future patients with this devastating disease. Given the enormous costs of ICH, problems with current therapies, and variability in treatment, there is an urgent need to identify a therapy that has a better safety and effectiveness profile compared to the currently used agents. This study will use a dose (40mg/day) currently approved. Further, given that the primary purpose of the use of this medication in this study is not to correct hyponatremia, an investigational new drug (IND) application to the FDA was submitted, and the study was determined exempt.

Our central hypothesis is that through reductions in aquaporin-4 (AQP4) expression, the early use of conivaptan will reduce CE while also being safe to the patient. Our long term goal is to show that early use of conivaptan in ICH will reduce CE. If this reduction is possible, we hypothesize improved outcome and reducing the need for rescue therapies, ICU length of stay, and overall treatment cost will follow. However, more data is needed to evaluate the dosing and amount of drug. With respect to conivaptan's efficacy in correction of hyponatremia, a direct dose-response relationship exists. Further, this effect was more noted at milder degrees of hyponatremia.

Arms: arm 1: All seven patients in this arm will receive conivaptan as described in Interventions.
Interventions: intervention 1: Conivaptan
Intervention descriptions: intervention 1: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.

The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.

Protocol documents:
Prot_000.pdf: 
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Protocol 
 
CONIVAPTAN FOR THE REDUCTION OF CEREBRAL 
EDEMA IN INTRACEREBRAL HEMORRHAGE – 
A Safety and Tolerability Study 
 
NSJC-1601 NCT03000283 
 
 
Funded by United Hospital Medical Education and Research Committee 
 
 
 
 
Principal Investigator: 
Jesse J. Corry, MD 
 
 
Co-Investigators: 
Ganesh Asaithambi, MD 
Arif Shaik, MD 
Jeff Lassig, MD 
 
Research Nurse: 
Amy Castle, RN 
 
Study Coordinator: 
Emily Marino, BS 
Bridget Ho, BA, CCRC 
 
United Hospital, part of Allina Health 
John Nasseff Neuroscience Institute, part of Allina Health 
333 North Smith Avenue 
St. Paul, MN 55102 
651-241-6550 


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TABLE OF CONTENTS 
Section 
Page 
1. Research Goal 
3 
2. Specific Aims 
3 
3. Background 
3 
4. Significance 
5 
5. Preliminary Studies and/or Data 
6 
6. Research Design and Methods 
6 
6.1. Study Design 
6 
6.2. Inclusion/Exclusion Criteria 
6 
6.2.1. Inclusion Criteria 
6 
6.2.2. Exclusion Criteria 
7 
6.3. Subject Recruitment 
7 
6.4. Sample Size 
7 
6.5. Study Testing Location 
8 
6.6. Consent and Enrollment Process 
8 
6.7. Why a patient should participate in this trial 
9 
6.8. Treatment with Conivaptan 
11 
6.9. Primary Assessments 
14 
6.10Secondary Assessments 
15 
7. Safety Variables 
15 
7.1. Risks and Benefits 
16 
7.2. Adverse Events 
16 
7.3. Serious Adverse Events 
17 
7.4. Adverse Events Reporting 
17 
8. Data Management 
17 
8.1. Data Reviewed 
17 
8.2. Data Entry & Database Completion 
18 
8.3. Data Sharing 
19 
9. Statistical Analysis 
19 
10. Study Oversight 
19 
11. IRB Review/Ethics/ Informed Consent 
19 
12. Confidentiality 
20 
13. References 
20 
14. Appendices 
24 


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1. Research Goal 
 
The goal of this study is to preliminarily determine/estimate feasibility and whether frequent and early 
conivaptan use, at a dose currently determined to be safe (i.e., 40mg/day), is safe and well-tolerated 
in patients with cerebral edema from intracerebral hemorrhage (ICH) and pressure (ICP). A further 
goal is to preliminarily estimate whether conivaptan at this same dose can reduce cerebral edema 
(CE) in these same patients. This study is also an essential first step in understanding the role of 
conivaptan in CE management. 
 
Hypothesis: The frequent and early use of conivaptan at 40mg/day will be safe and well-tolerated, 
and also reduce cerebral edema, in patients with intracerebral hemorrhage and pressure. 
 
 
2. Specific Aims 
 
Aim 1: Evaluate the feasibility of the proposed study methods. 
 
Subaim 1: Determine the efficiency of enrolling patients into the study. [Accomplished by 
tracking the number of patients asked to participate compared to the number of 
subjects enrolled into the study.] 
Subaim 2: Determine the efficiency of obtaining all the study required data and information. 
 
Aim 2: Estimate trends in the safety, tolerability, and efficacy of frequent and early conivaptan use 
(started within the first 48 hours from ICH symptom onset). 
 
Subaim 1: Estimate if frequent and early use of conivaptan is safe and well-tolerated. 
[Based on previous work demonstrating conivaptan safety in other models, the 
working hypothesis is that early and frequent use will be well-tolerated, with 
few, if any, adverse events.] 
Subaim 2: Evaluate the amount of adjunct osmotic therapy (i.e., mannitol, 
hypertonic saline) given throughout study period. 
Subaim 3: Evaluate whether conivaptan reduces the extent of cerebral edema. 
[The working hypothesis is that early conivaptan use will reduce the presence 
of AQP4 and limit the development, and thus consequences, of CE.] 
 
 
3. Background 
 
Intracerebral hemorrhage (ICH) represents ~10-15% of all strokes in the United States (U.S.), 
numbering 50-70,000 cases per year, twice as common as subarachnoid hemorrhage (SAH), the 30 
day mortality is ~40%, and greatest among the poor, elderly, black and Asian (Adams, 2005; Thomas 
et al., 1996). Only 20% of ICH patients are independent at 6 months. Only admission to a neuro-ICU, 
and the use of a CT scanner, have been shown to improve outcome from ICH (Thomas et al., 1996; 
Diringer & Edwards, 2001). With respect to cost, ICH represents 34% of years of potential life lost to 
stroke (Thomas et al., 1996).  Per case, the cost is ~$124,000, and the total lifetime cost for annual 
US cases >$4B (Thomas et al., 1996). 
 
Complicating ICH is the development of cerebral edema (CE). Worsening CE has been implicated in 
delayed neurological deterioration, and worse outcome, through the elevation of intracerebral 
pressure (ICP) (Mayer & Sacco, 1994). Elevations in ICP reduce the ability of blood to reach the 


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brain, exacerbating the injury and producing ischemia. The formation of peri-hematomal edema 
contributes to an increased volume of ~75% (Gebel et al., 2002). Animal models of ICH demonstrate 
a large peri-hematomal area that undergoes neuronal death characterized by increased water content 
and inflammation (Theix & Tsirka, 2007).  Reduction of this edema may reduce the degree of 
neuronal death, decreasing hospital length-of-stay (LOS), and improving short-term outcome (Volbers 
et al., 2016). 
 
Wide variability exists in the treatment of ICP and CE among intensivists (Hays et al., 2010). In part, 
this may be the function of training and/or experience. The use of mannitol, which elevates the 
osmolarity within the cerebral vasculature, promoting water movement across the blood-brain barrier 
and into the capillary system (Galton et al., 2011), is common, but is limited by its deleterious effects 
on renal function, fluctuations in intravascular volume, and pH. Most concerning is the slow 
elimination of mannitol from the cerebrospinal fluid (CSF) which may potentially require progressively 
higher doses, over time, to control ICP, and may result in rebound CE (Nau et al., 1997; McGraw & 
Howard, 1983). Increasingly, hypertonic saline (HS), which acts similar to mannitol, is being used to 
abate CE. However, this therapy has not demonstrated any survival or outcome benefit despite 
reductions in ICP (Bulger et al., 2010; Strandvik, 2009). And, currently, there is a national shortage of 
HS (FDA, 2010). A retrospective review of available data at Henry Ford Health System preliminarily 
demonstrates adverse effects on renal function with the use of HS (Corry et al, 2014). Further, 
anecdotal observations have noted changes in renal function and difficulty replacing free-water 
deficits (FWD) following aggressive antecedent use of HS. A known side-effect of HS therapy is 
hyperchloremia (HC). Chlorine is a potent renal vasoconstrictor potentially reducing blood flow, 
precipitating renal ischemia and reducing glomerular filtration rate (Wilcox, 1983; Gazitua et al., 1969). 
Finally, the use of HS may be associated with increased risk of blood-stream infections (BSI), and 
trends to increased risk of nosocomial and urinary tract infections (Bulger et al., 2010). 
 
In sum, neurocritical care needs a therapy that can reduce the development of CE, potentially 
decreasing ICU LOS and possibly improving outcome. Could a single medication reduce the CE in 
ICH and improve the treatment variability found in this disease process? Conivaptan, a non-selective 
Arginine-Vasopressin (AVP) V1A/V2 antagonist that reduces aquaporin 4 production, thus promoting 
aqueresis, is approved for the treatment of euvolemic and hypervolemic hyponatremia (Cumberland 
Pharmaceuticals, 2014). The early use of conivaptan could potentially be used clinically to reduce CE 
by these means.  Current clinical data in traumatic brain injury patients demonstrate conivaptan is 
safe and well tolerated using a single dose (20mg) to increase Na+ in a controlled fashion to reduce 
ICP (Galton et al., 2011; Dhar & Murphy-Human, 2011). Further, additional work has demonstrated 
the safety and tolerability of conivaptan, in doses ranging from 10-80mg/day, in the neurocritical care 
population (Ghali et al., 2006; Zeltser et al., 2007; Verbalis et al., 2008; Annane et al., 2009; Murphy 
et al., 2009; Wright et al., 2009; Naidech et al., 2010; Human et al, 2012; Marik & Rivera, 2013). 
 
AVP V(1) receptor antagonism significantly reduces hemorrhagic brain edema in rat models 
(Rosenberg et al., 1992). 
Traumatic brain injury (TBI) research, using animal models, has 
demonstrated V1 expression is increase in astrocytes and blood vessel endothelium during the first 
week following injury (Szmydynger-Chodobska et al., 2004). Experimental models have 
demonstrated AVP V(1) receptor antagonism attenuates injury volume, and CE, through changes in 
aquaporin-4 (AQP4) expression (Liu et al., 2010). Although not the exclusive means for water flux in 
the brain, AQP4 is the predominant class of water channel in the brain (Yool et al., 2010; Zeynalov et 
al., 2008). For edema to occur, water must enter the astrocyte compartment. Water must pass from 
the capillary lumen and through the luminal, abluminal, and luminal perivascular endothelium. The 
perivascular pool appears, in both the influx and efflux of water, to be the rate limiting step (Zeynalov 
et al., 2008). Inhibition of water permeability, via reductions in AQP4, decreases ipsilateral 
hemispheric water content and may have therapeutic potential for CE in the clinical setting (Migliati et 
al., 2010; Rosenberg et al., 1992). 


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Animal models have demonstrated AQP4 expression increases within 6 hours from injury, peaks 
between 48-72 hours, and remains elevated over the first week (Li & Sun, 2003; Sun et al., 2009). 
This increased expression parallels brain water content (BWC) in hemorrhagic animal models. 
Antagonism of AVP V(1), in animal models of TBI and both hemorrhagic and ischemic stroke, is 
associated with parallel reductions of AQP4 expression and CE as measured by BWC (Liu et al., 
2010; Taya et al., 2008; Trabold et al., 2008; Rosenberg et al., 1992). 
 
Recently, bolusing of conivaptan (20mg) has been shown to lower ICP in hyponatremia following TBI 
and cerebral ischemia (Dhar & Murphy-Human, 2011; Galton et al., 2011). The authors reported 
improvements in cerebral perfusion pressure (CPP) and stable blood pressure, and a prolonged 
reduction in ICP. They theorize the V2 antagonism of conivaptan promotes free water loss to reduce 
BWC, and the V1 antagonism may improve cerebral blood flow (CBF) and reduce blood brain barrier 
permeability (Taya et al., 2008; Trabold et al., 2008; Dhar & Murphy-Human, 2011; Vakili et al., 2005; 
Kleindienst et al., 2006; Fernandez et al., 2001 ). 
 
Given the enormous costs of ICH, problems with current therapies, and variability in treatment, there 
is an urgent need to identify a therapy that has a better safety and effectiveness profile compared to 
the currently used agents. Our central hypothesis is that through reductions in AQP4 expression, the 
early use of conivaptan will reduce CE while also being safe to the patient. Our long term goal is to 
show that early use of conivaptan in ICH will reduce CE, thus improving outcome and reducing the 
need for rescue therapies, ICU length of stay, and overall treatment cost. However, more data is 
needed to evaluate the dosing and amount of drug. With respect to conivaptan’s efficacy in the 
correction of hyponatremia, a direct dose-response relationship exists (Onuoho et al., 2010). Further, 
this effect was more noted at milder degrees of hyponatremia, suggesting higher doses may be 
required to achieve a hypernatremic state (Onuoho et al., 2010). However, whether the reduction in 
CE parallels the relative changes in serum sodium remains to be determined. The objective of this 
proposal is to first establish whether conivaptan use, at a dose currently determined as safe (i.e., 
40mg/day), can reduce CE. This proposed study is an essential first step in understanding the role of 
conivaptan in CE management. Prior to any mechanistic investigations, a fundamental understanding 
of dosing and toleration must occur. If this proof-of-concept study demonstrates the desired effect, 
work can take place identifying the optimal dosing and frequency needed for maximal effect. Later 
studies could ask questions on efficacy. Further, should such studies prove fruitful, mechanistic 
investigations using MRI and microdialysis could elucidate effects on membrane integrity, 
inflammation, and secondary cell injury. 
 
 
4. Significance 
 
As stated above, there are enormous costs involved with ICH, there is variability in its treatments, and 
many of the current therapies can cause serious side effects. A new, safe and effective therapy is 
needed. Conivaptan was approved by the FDA ~11 years ago for the treatment of euvolemic and 
hypervolemic hyponatremia. Since then, it has been used safely in doses ranging from 10-80 mg/day 
for this treatment. An additional benefit observed has been the reduction of ICP in a number of 
patients. However, more work is needed to determine the appropriate amount of drug, dosing 
schedule, etc. needed for the maximal effect on CE. This proposed study is an essential first step in 
that direction. 
 
 
5. Preliminary Studies and/or Data 


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Dr. Corry received his MD degree from the Medical College of Wisconsin in 2002. Remaining at the 
Medical College of Wisconsin Affiliated Hospitals, he completed an Internal Medicine Internship in 
2003 and a Residency in Neurology in 2006. He went on to complete a Fellowship in Neurocritical 
Care at Washington University School of Medicine in St. Louis, Missouri, in 2008. He practiced at 
Henry Ford Hospital in Detroit and at Marshfield Clinic in Wisconsin prior to joining the John Nasseff 
Neuroscience Specialty Clinic at United Hospital. As neurovascular physician, Dr. Corry is familiar 
with the physiology and clinical consequences of CE, as well as the limitations of available medical 
and surgical interventions. On the topic of CE, Dr. Corry has studied the renal effects of HS, and 
published on methods to mitigate the deleterious effects of CE. Publications include: 
 
Corry JJ, Varelas P, Abdelhak T, Morris S, Hawley M, Hawkins A, Jankowski M. Variable Changes in 
Renal Function by Hypertonic Saline. World Journal of Crtical Care Medicine. 2014 May 4; 3(2): 61- 
67. 
 
Corry JJ. The use of targeted temperature management for elevated intracranial pressure. Curr 
Neurol Neurosci Rep. 2014 Jun;14(6):453. 
 
Corry JJ. Use of hypothermia in the intensive care unit. World J Crit Care Med. 2012 Aug 4;1(4):106- 
22. 
 
 
6. Research Design and Methods 
 
 
6.1 Study Design: a single-center, open-label, safety and tolerability study. 
 
Based on findings in the literature from both animal research and clinical observations with ICH 
associated with TBI, this study will begin to look at the safety, tolerability, as well as potential 
effectiveness, of conivaptan to reduce CE in patients with non-traumatic ICH. 
 
 
6.2 Subjects and Inclusion/Exclusion Criteria 
 
Patients with non-traumatic ICH admitted to the United Hospital Neurological Intensive Care Unit 
(Neuro-ICU). The 2016 ICD-10-CM diagnosis code for ICH is 161.9 Non-traumatic ICH generally 
results from the rupture of blood vessels in the brain, causing blood to collect, form a clot and cause 
pressure to surrounding tissue. This is most commonly due to hypertension, blood vessel 
malformation(s), and/or dysfunctional protein(s) leading to weak vessels. The presenting behavior is 
quite similar with symptoms such as headache, nausea, vomiting, sudden weakness or numbness of 
the face, arm or leg, temporary loss of vision, seizures, and/or loss of consciousness. Approximately 
2/3rds of all ICH’s have a volume greater than 20cc. 
 
 
6.2.1 Major Inclusion Criteria 
1. Age ≥18 years old and < 80 years. 
2. Diagnosis of primary ICH > 20 cc in volume. 
3. Enrollment within 48 hours from initial symptoms. 
4. Signed informed consent from the patient or obtained via their legally authorized 
representative (if the patient is not able to sign the informed consent themselves). The 
patient’s decisional capacity to either provide or refuse consent will be determined using 
the Glasgow Coma Scale (GCS), which is being assessed at baseline and at 24 hours (+/- 
6hrs) after enrollment. A potential study participant with a GCS > 14 will be asked to 


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provide their own initial study consent. A GCS ≤ 14 would indicate the need to pursue 
consent via legally authorized representative. Patient and/or LAR must be English 
speaking. 
 
 
6.2.2 Major Exclusion Criteria 
1. Current need for renal replacement therapy (RRT). 
2. GFR of <30 mL/minute at time of admission. 
3. Participation in another study for ICH or intraventricular hemorrhage. 
4. ICH related to infection, thrombolysis, subarachnoid hemorrhage, trauma or tumor. 
5. Presence of HIV or active fungal infection that is known based on information in the EMR. 
6. Continued use of digoxin or amlodipine (as recommended by the manufacturer due to 
CYP3A inhibition). 
7. Active hepatic failure as defined by AST >160 units/L and/or ALT >180 units/L, or total 
bilirubin levels greater than four times normal levels (>4.8mg/dL). 
8. Serum Na+> 145 mmol/L (admission labs or any time prior to recruitment/enrollment). 
9. Unable to receive conivaptan based on contraindications indicated by the manufacturer. 
10. Pregnant or lactating females. 
11. Not expected to survive within 48 hours of admission, or a presumed diagnosis of brain 
death. 
 
 
6.3 Subject Recruitment 
 
The PI, co-investitagors and study team members, will screen and recruit participants from the non- 
traumatic ICH patient population admitted to the United Hospital Neuro-ICU meeting the study 
inclusion and exclusion criteria. Investigators will only screen patients seen as part of their normal 
clnical practice in the Neuro-ICU. Other physicians in Neurology and the Neuro-ICU will be informed 
of the study by an informational letter sent by the PI, and/or during departmental meetings where the 
PI will discuss the study. An informational letter, list of inclusion and exclusion criteria and a study 
binder will also be housed in the Neuro-ICU for reference. 
 
 
6.4 Sample Size 
 
This study is looking to preliminarily evaluate the safety, tolerability, and efficacy (presence of 
moderate reduction in CE), and as a ratio of ICH volume to CE volume. Unfortunately, it is not 
powered to provide robust statistical evaluation of safety and tolerability, nor to detect differences in 
efficacy, due to time and budgetary limitations. 
 
Seven (7) patients will be treated with conivaptan (40mg/day; four 20mg doses over a 2 day period) in 
addition to conventional medical means. This number of patients takes into account information in the 
conivaptan in TBI patients study by Galton et al (2011), use of glyburide in ICH by Sheth et al. (2014), 
as well as time and budgetary limitations. 
 
The goal is to enroll all seven (7) patients within an 18-month period. This recruitment goal should be 
achievable since: 
1) according to the PI’s experience, (based on 2015 data) ~50-70 ICH patients (ICD-10-CM 
code 161.9) are admitted per year to United Hospital and 
2) according to a recent electronic feasibility search, in the year 2015, 55 patients with a 
diagnosis of ICH were admitted to United Hospital. Of these patients, the PI determined that 9 
would have been eligible for the study, based on the study’s inclusion and exclusion criteria. 


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6.5 Study Testing Location 
 
Neurological Intensive Care Unit (Neuro-ICU) at United Hospital, part of Allina Health, 333 North 
Smith Avenue, Saint Paul, MN 55102. 
 
 
6.6 Consent and Enrollment Process 
 
Patients meeting inclusion criteria, and not possessing any exclusion criteria, will be approached or 
will have their healthcare advocate (e.g., legally authorized representative or LAR) approached by a 
member of the study team (e.g., PI, Co-I, research coordinator). 
 
Consent will need to be obtained within 48 hours of the patient’s symptoms onset. This consent can 
take place at the patient’s bedside, in another room in hospital, in a conference room, or over the 
phone, depending on whether it is with the patient or their LAR. The consent can occur potentially 
any day of the week; accomplished by the PI, Co-I, and/or RC during the week, and by the PI and/or 
Co-I on weekends. A consenting schedule will be developed, and training on the consent process will 
occur, prior to the start of the study. 
 
An explanation of the purpose of the study will follow conformation the subject meets all study criteria 
listed above. These steps may be performed by the PI, Co-I, and/or the research coordinator. 
 
The consent, along with HIPAA authorizations, will be explained and then signed by the patient or 
their LAR if they want to participate/want the patient to participate. A copy of the signed consent and 
the HIPAA authorizations will be given to the patient/participant’s LAR. Another copy will be uploaded 
to the patient’s electronic medical record, while the original forms will be kept in a locked file cabinet 
which is only accessible to study personnel. 
 
The consenting process will take ~ 1 hour. 
 
The patient/their LAR will be able to ask questions at any time during the consenting process and the 
study procedures. 
 
Those patients who decline enrollment/whose LAR decides to decline their enrollment will be given 
the standard of care for CE. 
 
If the patient or their LAR consents to the patient’s study enrollment, the patient will be assigned a 
study subject number, such as the patient’s day of enrollment and the first 2 letters of their last name 
(e.g., patient Joe Smith admitted on March 31, 2008 would be subject #033108SM). 
 
The PI will share any new information that could change how the patient feels about continuing in the 
study. 
 
If during the course of the study a subject regains consciousness and their decisional capacity (i.e., a 
GCS > 14), especially at any of the study assessment time points, they will be asked if they want to 
consent to continuing in the research study. 
 
If a patient decides to withdraw for any reason during the study duration or the LAR wants to withdraw 
a patient for any reason during the study duration, the patient’s data collected up to point of withdrawl 


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will remain in the database and will be analyzed. If the patient/LAR is against any of the data being 
used, we will grant this request. 
 
The PI may withdraw the subject from the study without patient/LAR consent if considered 
appropriate. The reason to withdraw would include complications related to the use of conivaptan. 
For safety, if withdrawn from the study, it would be in the best interest of the patient to allow follow-up 
outside the study. 
 
The consent will explicitly detail all aspects of the study (the purpose, methods, benefits, risks). 
 
 
6.7 Why a patient should participate in this trial? 
 
ICH is a devastating disease representing approximately 15% of all strokes in the United States 
(Adams 2005, Thomas et al 1996). The 30 day mortality is ~ 40% with only admission to a neuro-ICU 
and the use of a CT scanner demonstrating improved outcomes (Thomas et al., 1996; Diringer & 
Edwards, 2001). Nearly as great are the costs to society, with the total lifetime cost for annual US 
cases >$4B and nearly 35% of years of potential life lost because of stroke (Thomas et al., 1996). 
This devastation is influenced by the dynamic injury processes involved in ICH. Following the initial 
hemorrhagic injury, CE develops. This peaks between 7-14 days after the initial bleed 
(Venkatasubramanian 2011). Worsening CE has been implicated in delayed neurological 
deterioration, and worse outcome, through the elevation of ICP (Mayer & Sacco, 1994). Elevations in 
ICP reduce the ability of blood to reach the brain, exacerbating the injury and producing ischemia. 
The formation of peri-hematomal edema contributes to an increased volume of ~75% (Gebel et al., 
2002). Animal models of ICH demonstrate a large peri-hematomal area that undergoes neuronal 
death characterized by increased water content and inflammation (Theix & Tsirka, 2007). Reduction 
of this edema may reduce the degree of neuronal death, potentially improving outcome and 
decreasing hospital LOS. Further, a shorter time in the neuro-ICU, much of which is focused on 
management of CE, would mean decreased hospital costs in the form of less nosocomial infections. 
 
Studies in neurocritical care are often limited in their design and scope because many of the common 
therapies, despite a paucity of clinical evidence, are considered “standard of care.” (Chesnut, 2012). 
This holds true in the management of CE and ICP, where a wide variability in treatment exists among 
intensivists (Hays et al., 2010). The two most commonly used agents for the medical management of 
CE and elevated ICP, mannitol and hypertonic saline, do not demonstrate any evidence of improving 
clinical outcome (Grande, 2012). Mannitol use is common, but is limited by its deleterious effects on 
renal function, and fluctuations in intravascular volume and pH. Most concerning is the slow 
elimination of mannitol from the CSF which may potentially require progressively higher doses, over 
time, to control ICP, and may result in rebound CE (Nau et al., 1997; McGraw & Howard, 1983). 
Increasingly, HS is being used to abate CE. However, this therapy has not demonstrated any survival 
or outcome benefit despite reductions in ICP (Bulger et al., 2010; Strandvik, 2009). The use of 
hypertonic saline may be associated with increased risk of BSI, and trends to increased risk of 
nosocomial and urinary tract infections (Bulger et al., 2010). Recently, a retrospective review of 
patients receiving HS in a single center’s neurocritical care unit demonstrated a correlation between 
the degree of hypernatremia and hyperchloremia induced by HS and changes in renal function 
heralding the development of acute kidney injury (Corry et al., 2014). Therefore, any new therapy for 
CE in ICH should have less or equivalent side effects to mannitol and HS. 
 
It is with this balance in mind, the need for effective therapies in a devastating disease and the 
continued use of historically approved therapies, that this study is proposed. The welfare of our 
patients is the primary goal of this trial. Our first goal Primum non nocere, to do no harm, is central to 
this study (Ross, 1988). All patients will receive the standard of care as outlined by the most recent 


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American Heart Association and Neurocritical Care Society Guidelines for the management of ICH. 
This will include, but not be limited to, serial clinical and paraclinical evaluations including CT scans, 
metabolic profile, echocardiography, etc. Current standards-of-practice, including euvolemia targets, 
electrolyte replacement, venous thrombosis prophylaxis, normoglycemia, etc. will be maintained in 
this population. The risks most commonly seen with conivaptan use are hypotension (associated with 
volume loss), site reactions, and electrolyte abnormalities including hypokalemia and 
hypomagnesemia that may result in dysrhythmia. Thus, patients will be closely monitored for these 
and other problems. Finally, to evaluate for any unforeseen problems with the use of this medication, 
these patients will receive standard of care practice, including neuroimaging and outpatient clinic 
follow-up. 
 
The seven patients in this study will receive 40mg/day of the study medication conivaptan. In this 
early phase study, our focus will be to assess the safety and tolerability of this medication. The 
available clinical data on conivaptan in the neurocritical care population suggest the potential harm is 
negligible. Data in TBI patients demonstrate conivaptan is safe and well tolerated using a single dose 
(20mg) to increase Na+ in a controlled fashion to reduce ICP (Galton et al., 2011). Previous work has 
demonstrated the safety and tolerability of conivaptan, in doses ranging from 20-80mg/day, in the 
neurocritical care population (Murphy et al., 2009; Wright et al., 2009; Naidech et al., 2010; Dhar & 
Murphy-Human, 2011). Conivaptan has been demonstrated to be safe and effective in lowering ICP, 
and increasing serum sodium, in the neurocritical care population (Murphy NCC ’09, Wright NCC ’09, 
Dhar NCC ’11, Galton NCC ’11). Also noted have been improvements in CPP and stable blood 
pressure, and a prolonged reduction in ICP. Finally, the method of intermittent bolus dosing of 
conivaptan is equally effective in raising and maintaining serum sodium in the neurocritical care 
population as continuous infusion, with potentially less risk of adverse reactions including phlebitis 
(Murphy NCC ’09, Wright NCC ’09). 
 
Conivaptan, a non-selective Arginine-Vasopressin (AVP) V1A/V2 antagonist that reduces aquaporin 4 
production and promotes aqueresis, is approved for the treatment of euvolemic and hypervolemic 
hyponatremia (Cumberland Pharmaceuticals, 2014). The exact cause of the observed reduction in 
ICP with conivaptan is uncertain. However, the mechanism most likely represents a combination of 
an acute pure aquaresis, removing free water from brain tissue, and a sustained down regulation of 
aquaporin 4 to abate/slow development of CE (Dhar NCC ’11, Liu X NCC ’10, Zandor Handb Exp 
Pharmacol. 2009). The V2 antagonism of conivaptan promotes free water loss, and the V1 
antagonism may improve CBF and reduce blood brain barrier permeability (Taya et al., 2008; Trabold 
et al., 2008; Dhar & Murphy-Human, 2011; Vakili et al., 2005; Kleindienst et al., 2006; Fernandez et 
al., 2001 ). Notably, serum sodium tends to correlate inversely with both ICP and CE (Nathan NCC 
’07). The early use of conivaptan could potentially be used clinically to reduce CE by these means. 
 
It is with this in mind, the research team feels justified in pursuing this study with the hopes that the 
data obtained will lead to potential good and removal of harm in future patients with this devastating 
disease. Given the enormous costs of ICH, problems with current therapies, and variability in 
treatment, there is an urgent need to identify a therapy that has a better safety and effectiveness 
profile compared to the currently used agents. This study will use a dose (40mg/day) currently 
approved. Further, given that the primary purpose of the use of this medication in this study is not to 
correct hyponatremia, an IND from the FDA was sought and determined exempt (FDA IND 
submission/exemption # 119424). 
 
Our central hypothesis is that through reductions in AQP4 expression, the early use of conivaptan will 
reduce CE while also being safe to the patient. Our long term goal is to show that early use of 
conivaptan in ICH will reduce CE. If this reduction is possible, we hypothesize improved outcome and 
reducing the need for rescue therapies, ICU length of stay, and overall treatment cost will follow. 
However, more data is needed to evaluate the dosing and amount of drug. With respect to 


Protocol NSJC-1601 NCT03000283 
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conivaptan’s efficacy in correction of hyponatremia, a direct dose-response relationship exists 
(Onuoho et al., 2010). Further, this effect was more noted at milder degrees of hyponatremia, 
suggesting higher doses may be required to achieve a hypernatremic state (Onuoho et al., 2010). 
This proposed study is an essential first step in understanding the role of conivaptan in CE 
management. Prior to any mechanistic investigations, a fundamental understanding of dosing and 
toleration must occur. If this study demonstrates the desired effect, work can take place identifying 
the optimal dosing and frequency needed for maximal effect. Later studies could ask questions on 
efficacy. Should such studies prove fruitful, mechanistic investigations using MRI and microdialysis 
could elucidate effects on membrane integrity, inflammation, and secondary cell injury. 
 
Prior clinical experience suggests patients enrolled in this study will not be harmed.  However, 
patients enrolled may not be helped by participating in this study either; others may be helped by what 
is learned from this research. Patients initially enrolled, or their LAR, may stop participation at any 
time. If this happens, they will still be followed-up for safety reasons. Patients will receive the same 
medical care whether or not they participate in this study. There will be no penalties or loss of benefits 
if patients choose not to participate. Patients will be told about any significant information that is 
discovered that could reasonably affect their willingness to continue being in the study. Finally, we do 
not expect there to be any additional costs to the patients if they participate in this study. Items related 
to the routine medical care that patients would receive even if they did not participate in this study will 
be billed to their insurance provider. Finally, there will be no compensation for participation in this 
study. 
 
 
6.8 Treatment with Conivaptan 
 
Note: An Investigational New Drug (IND) application for this label use of conivaptan has be submitted 
to the FDA. After extensive discussions, it was felt this use at this dose did not require an IND (FDA 
IND submission/exemption # 119424). 
 
Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 
doses total), in addition to the standardized ICH management targets using the PI’s version of 
standardized ICH management targets which are adapted from the 2015 AHA/ASA Guidelines for the 
Management of Spontaneous Intracerebral Hemorrhage and the 2007 Brain Trauma Foundation 
Head Injury Guideline. This will ensure that all the patients will be managed similarly, to decrease the 
potential for variability commonly seen in “standardized” treatments. Usual standard of care can 
include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as 
needed to reduce ICP, and temperature control with antipyretics such as acetaminophen. 
 
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused 
(peripherally) over 30 minutes, most commonly through an already placed central line. The 
conivaptan will be ordered through the hospital’s clinical pharmacy. Daily doses greater than the 
40mg/day dose being used in this study (i.e., 80mg/day) have been shown to be safe in several 
studies (Zeltser et al., 2007; Verbalis et al., 2008; Annane et al., 2009; Ghali et al., 2009). 
 
Seven (7) patients will be receiving conivaptan in addition to standardized management. 
 
Electrolytes (obtained from a comprehensive metabolic panel, magnesium, & phosphorus test) will be 
drawn 6 hours after every conivaptan dose (4 total doses over 2 days). However, these labs may be 
done sooner (e.g., 2 hours after a conivaptan dose) based on the patient’s progress/need and/or the 
attending physician’s direction. The comprehensive metabolic panel will be utilized for these 4 
analyses due to its incorporation of several additional parameters (over the basic metabolic panel) 
needed for the study. The study will cover the costs of this. If the patient’s serum Na+ becomes > 160 


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mmol/L, or increases >12 mmol/L in a 24 hour period, further administration of the study drug will 
cease. If the patient has not completed the sequence of doses, they will be eligible for the remaining 
doses if their serum sodium falls below the threshold of 150 mmol/L, or after 24 hours in the case of 
increases of >12 mmol/L. Need for further use of hypertonic saline or mannitol is left to discretion of 
the treating physician 
 
All patients will have CT scans at baseline and ~24, 72, and 168 hours (7 days) from enrollment to 
check for bleeding, lasting edema, or rebound edema. An 8 hour variance is permitted. It is 
preferable that the CT scans be done at 3mm increments as this is helpful for volume analysis, but 
5mm is acceptable. Further imaging is left to the discretion of the treating/primary service physician. 
 
Electrolytes (standard-of-care, basic metabolic panel) for all subjects/patients will be measured every 
12 hours for the first 72 hours of the study, and then daily after 72 hours. This is considered a regular 
schedule based on clinical need. However, during the ~48 hour period when the subjects are 
receiving conivaptan, a comprehensive metabolic panel, Mg, and PO4 will be drawn and analyzed 6 
hours after each conivaptan dose. These labs may be done sooner based on the patient’s 
progress/need and/or the attending physician’s direction. 
 
Neurological exams (e.g., EEGs), vital signs, and urine output measurements will be conducted as 
per Neuro-ICU protocol. 
 
The need for ancillary monitoring tools (i.e. EVDs, bolts, microdialysis, EEG, near-infrared 
spectroscopy) will be at the discretion of the treating physicians. 
 
No statin will be initiated within the 1st week following treatment with conivaptan. And, all statin 
medications will be held from enrollment to day 7 following conivaptan in patients selected for the 
study. Statins can promote hemorrhage. Those patients who are in-eligible or refuse the study will 
resume/assume statin use at the treating physician’s discretion. 
 
Neuro-ICU personnel/nurses will assist the PI and Co-I with patient care following both standard-of- 
care and study parameters as part of their normal duties, to maintain the flow of excellent patient care. 
Therefore, they are not listed on the study budget as study personnel. 


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Table 1. Project Schema 
Assessment 
Baseline 
Enrollmentb 
(within 48 hrs 
of onset) 
6 hours from 
dose 
12 hours 
from 
enrollment 
6 hours from 
dose 
24 hours 
from 
enrollment 
6 hours from 
dose 
36 hours 
from 
enrollment 
6 hours from 
dose 
72 hours 
from 
enrollment 
Days 3-6 
Day 7 
Discharge 
Follow-up 
Inclusion/ 
exclusion 
criteria 
Xa 
Consent 
Process 
Xa 
Patient 
demographics 
Xa 
Medical history 
Xa 
Clinical Assessment 
GCS 
Xc 
Xc 
Xc 
Xc 
Xc 
X ͥ 
APACHE II 
Xc 
mRS 
Xc 
Xc 
X ͥ 
ICH 
Xc 
RIFLE 
Xc 
Xc 
X ͥ 
Imaging 
CT scan (non- 
contrast) 
Xd 
Xd 
Xd 
Xd 
X ͥ 
Study Drug 
Conivaptan 
(20mg) 
Xf 
Xf 
Xf 
Xf 
Laboratory Tests 
Comprehensive 
metabolic Panel 
X 
Xe 
Xe 
Xe 
Xe 
Magnesium 
X 
Xe 
Xe 
Xe 
Xe 
Phosphorus 
X 
Xe 
Xe 
Xe 
Xe 
EMR Data Collectionh 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICP monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mannitol 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sodium 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication log 
X 
X 
X 
X 
Cardiac 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intake/Output 
X 
X 
X 
X 
X 
Adverse event 
log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X ͥ 
 
aOccurs prior to enrollment. Other standard-of-care activities that will have occurred (between hospital 
arrival to 6 hrs post-arrival): 1) CT +/- CTA/CTV, 2) identify and correct coagulopathy, 3) identify and 
correct blood pressure (BP), 4) identifiy and correct ICP, and 5) admission to Neuro-ICU. 


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bEnrollment needs to occur within 48 hrs from initial symptoms. 
 
cClinical assessments can be study only or standard-of-care activites with a time window of +/- 6 
hours. 
 
dAdmission and 24-hr stability CT scans are standard-of-care. Additional CT scans, other than the 
study related 72-hr and 7-day (168 hours) scans, may be done as clinically indicated by treating 
physician. All scans have a time window of +/- 8 hours. 
 
eDependent on conivaptan dose. Each needs to be drawn and analyzed 6 hours after each 
conivaptan dose. However, these labs may be done sooner (e.g., 2 hours after a conivaptan dose) 
based on the patient’s progress/need and/or the attending physician’s direction. Otherwise, standard- 
of-care labs (e.g., BMP) are drawn and analyzed every 12 hrs during the first 72 hrs after admission, 
followed by daily draws and analyses. 
 
fDependent on when the 1st of the 4 doses was started. 
 
hStandard-of-care information collected as part of normal clinical practice will be recorded from the 
electronic medical record. Information may be recorded on a daily basis or after the protocol is 
complete. 
 
ͥFollow-up visits will be conducted as part of normal clinical practice and information recorded, if 
available, from the electronic medical record. Three month post-discharge follow-up visits are 
standard-of-care. 
 
Note: Training and informational sessions covering all aspects of the study (e.g., patient enrollment, 
treatment, ordering of lab tests, data collecting, etc.) will be held prior to the start of the study. 
 
 
6.9 Primary Assessments (Safety and Tolerability) 
 
Conivaptan was approved by the FDA in 2005 for the treatment of euvolemic and hypervolemic 
hyponatremia in a hospitalized setting using doses of 20-40mg/day.  In the 11 years it has been on 
the market, numerous studies using it at doses ranging from 20-80mg/day have been done furthering 
the data on its effect on hyponatremia (National Monograph, 2006; Ghali et al., 2009; Zeltser et al., 
2007; Verbalis et al., 2008; Annane et al., 2009; Human et al., 2012; Marik & Rivera, 2013), as well as 
studies showing its lowering of ICP in patients with TBI (Dhar & Murphy-Human, 2011; Galton et al., 
2011). These benefits should relate to a decrease in CE. 
 
In all these studies, conivaptan was well tolerated and safe, with no drug-related serious adverse 
events observed. For example, in the Ghali et al (2009) study, no deaths were study related, and the 
side effects of headache, hypotension, nausea, and constipation occurred most frequently. 
Based on these observations, we expect only minimal, if any, side effects in our study, since we are 
using a dose (40mg/day) which is lower than the 80mg/day used in several of the above mentioned 
studies. And, we feel there are no special concerns in the patient population included in our study 
(non-traumatic ICH) since conivaptan has already been safely used in TBI ICH patients. 
 
An evaluation of the safety assessment parameters of each of the seven (7) subjects will be done by 
the PI and Co-I during the patient’s care. Should events occur regarding the administration of 
conivaptan that raise safety concerns, the PI has the authority to withdraw the subject and/or halt the 
study pending further investigation. 


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Specific safety assessment parameters will include the following- 
 
Neurologic tolerability: 
1. Seizure frequency (15-20% of patients with ICH have seizures associated; EEGs will be 
used and measured; all treatments will be the same, using anti-seizure drugs). 
2. Total Na+ mEq received. 
3. ICP variability. In all patients for whom ICP is monitored, the hourly mean and median ICP 
will be compared. Further, patients will be graphed and the area-under-the-ICP-curve and 
above 10, 15, and 20 mmHg will be calculated and averaged to provide a more continuous 
comparison. 
4. ICP response to osmotic therapy. In patients receiving mannitol or 23.4% NaCl boluses, 
the average ICP reduction in the hour following administration will be compared. 
5. Development of central pontine demyelination, expansion of initial ICH, new ICH or stroke. 
 
 
Cardiac tolerability: 
1. Troponin values. 
2. Development of new arrhythmia during ICU stay. 
 
 
Pulmonary tolerability: 
1. Development of pulmonary edema as determined by chest X-ray. 
2. Average PO2, FiO2, A-a gradient. 
 
 
Renal tolerability: 
1. Change in renal function/urine output. RIFLE criteria will be used to assess for 
development of renal dysfunction (Appendix 1). 
2. Need for renal replacement therapy (RRT). 
 
 
Infectious tolerability: 
1. Compare rates of BSI, VAP/HAP, UTI, and sepsis. 
 
 
In-hospital mortality stratified by APACHE II, GCS, and ICH Score. 
 
6.10 Secondary Assessments (Effectiveness) 
 
 
Reduction in CE as measured on CT. Goal is a 5-10% reduction in CE over time. Reduction 
will be measured both as absolute reduction, and as relative reduction, comparing the ratio of 
ICH to edema volume. The absolute edema reduction is more clinically relevant, while the 
ratio of ICH to edema volume has more research relevance, to aid in designing the next 
related studies. 
 
Outcome. mRS (Appendix 2) at discharge from ICU and from hospital stratified by APACHE II 
(Appendix 3), GCS (Appendix 4), and ICH Score (Appendix 5) 
 
Cost 
1. Length of stay in the neuro ICU. 
2. Need for EVD/bolt or surgical procedures (craniectomy, clot evacuation,VPS) for 
reduction/management of CE. 
3. Need for central venous lines, arterial lines, PICC lines, tracheostomy/PEGs. 
4. Duration on ventilator. 
5. Duration of EVD/bolt. 
 
7. Safety Variables 


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7.1 Risks and Benefits 
 
 
7.1.1 Potential risks 
 
Potential risks associated with conivaptan may include hypotension, excessive rise in serum sodium, 
development of central pontine myelinolysis, increase in seizure frequency, expansion of initial ICH, 
development of new ICH and/or stroke, development of new cardiac arrhythmia, development of 
pulmonary edema, change in renal function, and development of an infection. 
 
Potential risks involving blood draws may include temporary discomfort from the needle stick, pain or 
bruising, lightheadedness, and infection at the site. 
 
Potential risks of CT scans are exposure to radiation from X-rays, dizziness, cold sensation at 
injection site, worsening of poor kidney function, allergic reaction to injection dye, soreness or swelling 
at the injection site. 
 
Potential risks will be minimized by blood pressure monitoring, monitoring of total Na+ mEq received, 
EEG monitoring and measurement (15-20% of patients with ICH have seizures, anti-seizure 
medications will be used), ICH/ICP monitoring, monitoring of troponin levels, chest x-ray and 
monitoring of pulmonary parameters (such as PO2, FiO2, A-a gradient), assessment of renal function 
by the RIFLE criteria, monitoring for infections. 
 
Training sessions for all clinical study personnel will occur prior to the start of the study to discuss the 
potential risks that could occur, and the monitoring for and treatments that are in place. 
 
 
7.1.2 Potential benefits for the study subjects/society 
 
Because the current medications used have their own side-effects, participation may result in better 
reduction of the patient’s CE, and prevent/lessen the brain damage caused by CE/ICH, with less side 
effects from other typically used medications. 
 
The patients enrolled would help demonstrate if conivaptan is safe, well-tolerated, and effective in 
patients with CE. This knowledge will help further the understanding of this therapy, and its role in 
treating CE, as well as assisting with the designing of future clinical studies. 
 
 
7.2 Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a subject administered a study 
procedure. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of study procedures. 
Since this is a study involving an FDA drug, conivaptan, used for approved purposes, exempt from 
IND regulations, we do not anticipate adverse events to be a common occurrence in this research 
study. 
 
In case of such occurrence, for all AEs, the investigator will obtain adequate information to determine 
the following: 
• The appropriate descriptive term 
• Severity 


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• Onset/resolution dates and outcome. 
• Causality: the relationship of each AE will be defined as “unrelated” or “related” to study procedures: 
Unrelated: There is little or no possibility that the study procedures caused the AE; 
Related: There exists at least a reasonable possibility that the study procedures caused or contributed 
to the AE; an inability to identify an alternate etiology for an AE should not, by itself, justify a “related” 
attribution. 
• Whether it meets the criteria for classification as a SAE. 
 
 
7.3 Serious Adverse Events 
 
An SAE is any AE from this study that results in one of the following outcomes: 
• Death 
• Requires initial or prolonged inpatient hospitalization 
• Is life-threatening (that is, immediate risk of dying). 
• Is a persistent or significant disability/incapacity. 
• Other significant medical hazard. 
 
7.4 Adverse Events Reporting 
 
The investigator will document all directly observed AEs and all AEs spontaneously reported by the 
study subject. SAEs will also be reported to regulatory authorities in accordance with all applicable 
regulations, as appropriate. 
 
 
8. Data Management 
 
8.1 Data Reviewed 
 
 
Demographics: Age, race, gender, and risk factors (hypertension, diabetes, illicit drug use, 
coronary artery disease, stroke, alcohol use). 
 
Clinical Grading Scores: 
o Outcome: mRS (Appendix 2) at baseline and discharge (if available). This can be 
performed by study team or as part of normal clinical practice. 
o ICH score at baseline (Appendix 5). 
o GCS score at baseline, 24 hrs from enrollment, 72 hrs from enrollment 7 day and 
discharge (if available) (Appendix 4). 
o APACHE II at baseline (Appendix 3). 
 
Duration of Neruo-ICU and hospital stay. 
 
Need for any of the following: 
o EVD/Bolt. 
o Hemi-craniectomy. 
o Central venous line/PICC/Arterial line. 
o RRT. 
 
Concomitant osmotherapy: 
o Hypertonic saline. The total mEq delivered and form of delivery (i.e. NS vs. 3% NaCl 
solution vs 23.4% NaCl solution.) 
o Mannitol. Number of doses and total grams received. 
 
Concomitant medications 
 
Imaging evaluation: CT scans will be dichotomized and ICH volume and CE volume will be 
compared over time. The individual summed and averaged volumes, net ICH volume and 
edema volumes will be compared. A board certified/eligible radiologist will calculate serially 


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the hemorrhage volume on CT during the study period. ICH volume will be serially assessed 
both by the (AxBxC)/2 method and by volumetric calculations using volumetric software. Serial 
assessments of edema will occur by measurements of the length and width of regional edema 
in the CT slice demonstrating the greatest amount of edema. Volumetric calculations using 
volumetric software will also be employed to evaluate for CE volume. Further, the same 
measurements one slice above and below will be performed to allow for a volumetric 
comparison. Completed CT scan measurements and calculations will be e-mailed to the 
research coordinator for data entry. In addition to the planned imaging and chemistry panels, 
any other imaging or basic laboratory work, deemed medically necessary for patient care 
outside the study, will be evaluated in the final analysis. 
 
 
Clinical data collected from time of ICU admission to day 7: 
 
Vital signs (BP, HR, Temp) 
 
Daily weights and admission height 
 
ICP/CPP values- when available/when a monitor is being used 
 
CVP values- when available 
 
Volumes for intake and output. 
 
Na+ values 
 
Cl- values 
 
Cr values 
 
BUN values 
 
PO2 values- when available 
 
PCO2 values-when available 
 
A-a gradient- when available 
 
Urinalysis results-when available 
 
All culture results 
 
Data sources will include medical records, lab results, device reports, and vital signs. Information 
from Excellian will need to be obtained within a couple days of the patient leaving the Neuro-ICU. 
 
We have the support of the Neuro-ICU nurses/personnel through the Neuro-ICU unit manager Chirs 
Allen, RN. The research coordinator will stop by each subject’s room 1-2x/day during the patients 
study duration to confirm safety assessments are being monitored, and to collect data and 
information. 
 
 
8.2 Data Entry & Database Completion 
 
All completed data collection forms will be sent to the data entry person for entry into the study 
database. 
 
All paper forms will be stored in a locked cabinet, with only the study personnel knowing the location 
of the key. 
 
All database & study computers will be password-protected, with only the study team members 
knowing the password. 
 
Following completion of the database, random data validation by manual re-entry will occur to ensure 
the accuracy of previous data and information entry. 


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All patient identifiers will be deleted. Electronic data will be stored in a protected server accessible 
only to team members. Paper forms will be stored in a locked file in the PI’s JNNI office. Upon 
completion of the study, all paper forms will be destroyed. 
 
The completed & validated de-identified database will then be delivered to the biostatistician for 
statistical analyses to be performed. 
 
 
8.3 Data Sharing 
 
1) The results obtained from this study will be prepared within a manuscript for submission to a peer- 
reviewed journal. 
 
2) The results will also be used as preliminary data for future studies, including a rigorous, controlled 
study of the efficacy and safety of conivaptan compared to traditional treatments/a phase II dosing 
study. 
 
 
9. Statistical Analysis 
 
Descriptive statistics will be used to summarize the baseline characteristics and the outcomes, such 
as adverse events and the hospital length of stay. In addition, Mixed model with unequally spaced 
repeated measures will be performed to evaluate the change of the variables with unequally spaced 
repeated measures, such as edema content, ICH score, GCS score, and APACHE II score, where 
unequally spaced repeated edema content measurements for 7 patients will be plotted; while Mixed 
model with equally spaced repeated measures will be performed to analyze the change of the 
variables with equally spaced repeated measures, such Mg and PO4. 
 
 
10. Study Oversight 
 
The PI and the research team will be responsible for all safety assessments. Safety will be assessed 
for all patients enrolled in an ongoing fashion based on the incidence of AEs, SAEs, and treatment 
discontinuations due to AE. If any significant safety issues arise, a decision to modify or terminate the 
trial will be made. If requested, the study will be made available for monitoring, auditing, IRB review, 
and regulatory inspection by providing direct access to study related source data to oversight bodies 
like FDA. 
 
 
11. IRB Review/Ethics/Informed Consent 
 
ICH GCP guidelines require that all investigational studies be conducted under the auspices of an 
IRB/EC. This committee will approve all aspects of the study, including the protocol and informed 
consent to be used and any modifications made to the protocol or informed consent. The investigator 
will retain a copy of the communication from the IRB/EC to the investigator indicating 
approval/favorable opinion of the protocol and consent form. All changes to the protocol or consent 
form will be reviewed and approved prior to implementation, except where necessary to eliminate 
apparent immediate hazards to human patients. The investigator will also be responsible for obtaining 
periodic IRB/EC re-approval throughout the duration of the study. Copies of the investigator’s periodic 
report to the IRB/EC and copies of the IRB/EC’s continuance of approval will be retained in the site 
study files. 


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A sample informed consent form will also be provided to the IRB/EC. Prior to the beginning of the 
study, the investigator will obtain the IRB/ECs written approval/favorable opinion of the written 
Informed Consent Form and any other written information to be provided to patients. The written 
approval of the IRB/EC together with the approved subject information/Informed Consent Forms will 
be filed in the study files. The Informed Consent Form will contain all elements required ICH Good 
Clinical Practices (GCP) Guidelines in addition to other elements required by federal, state, local or 
institutional policy. The investigator will be responsible for obtaining an Informed Consent signed by 
each subject or his/her legally authorized representative, prior to his/her participation in the study, in 
accordance with ICH GCP guidelines. Informed Consent will be obtained from a subject or his/her 
legally authorized representative after a full explanation of the purpose of the study, the risks and 
discomforts involved, potential benefits, etc., have been provided by the investigator or designee, both 
verbally and in writing. The investigator is responsible to see that informed consent is obtained from 
each subject or legal representative and to obtain the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures. Participation in the 
study and date of informed consent given by the subject will be documented appropriately in the 
subject’s files. 
 
The original or copy of the signed copy of the Informed Consent will be maintained in the institution’s 
records. The subject or his/her legally authorized representative will also be given a copy of the 
signed consent form. 
 
 
12. Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. Subject names will not be 
retained in the database after completion of data collection and not used during any data analysis. 
Only the subject number will be recorded in the study database, and if the subject name appears on 
any other document (eg. radiology report), it will be obliterated before a copy of the source document 
is retained. Study findings stored on a computer will be stored in accordance with local data protection 
laws. The patients will be informed in writing that representatives of the sponsor, EC/IRB, or 
Regulatory Authorities may inspect their medical records to verify the information collected, and that 
all personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. If the results of the study are published, the subject’s 
identity will remain confidential. 
 
13. References (alphabetical order) 
 
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Annane D, Decaux G, Smith N for the Conivaptan Study Group. Efficacy and safety of oral 
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Bulger EM, May S, et al. Out of Hospital Hypertonic Resuscitation Following Severe Traumatic Brain 
Injury: A Randomized Controlled Trial. Journal of the American Medical Association. 2010; 304: 
1455-1464. 
 
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Corry JJ. The use of targeted temperature management for elevated intracranial pressure. Curr 
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Gazitua SJB, Scott JB, Chou CC, Haddy FJ. Effect of Osmolarity on Canine Renal Vascular 
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spontaneous intracerebral hemorrhage. Stroke. 33: 2631-2635, 2002. 
 
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Grande PO, Romner B. Osmotherapy in brain edema: a questionable therapy. J Neurosurg 
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Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH Score: A simple, reliable 
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antagonist SR49059 on brain edema formation following middle cerebral artery occlusion in the rat. 
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Critical Care Medicine. 15(9): 538-41, 2003 [English abstract]. 
 
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volume, brain water content, and aquaporin-4 expression following experimental stroke. Neurocritical 
Care. 12(1):124-31, 2010. 
 
Marik PE, Rivera R. Therapeutic effect of conivaptan bolus dosing in hyponatremic neurosurgical 
patients. Pharmacotherapy 2013; 33(1):51-55. 
 
Mayer, S A. Sacco RL. Neurologic deterioration in noncomatose patients with supratentorial 
intracerebral hemorrhage. Neurology. 44(8):1379-84, 1994. 
 
McGraw, C. P., & Howard, G. (1983). Effect of mannitol on increased intracranial pressure. 
Neurosurgery, 13(1):269-271. 
 
Migliati ER, Amiry-Moghaddam M, et al. Na(+)-K (+)-2Cl (-) cotransport inhibitor attenuates cerebral 
edema following experimental stroke via the perivascular pool of aquaporin-4. Neurocritical Care. 
13(1):123-31, 2010. 
 
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neurointensive care unit. Neurocritical Care. 11(1):14-9, 2009. 
 
Naidech AM. Paparello J. Leibling SM. Bassin SL. Levasseur K. Alberts MJ. Bernstein RA. Muro K. 
Use of Conivaptan (Vaprisol) for hyponatremic neuro-ICU patients. Neurocritical Care. 13(1):57-61, 
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Nau, R., Desel, H., Lassek, C., Thiel, A., Schinschke, S., Rossing, R., et al. (1997). Slow elimination 
of mannitol from human cerebrospinal fluid. European Journal of Clinical Pharmacology, 53(3):271- 
274. 
 
Onuoho A, Human T, Dringer MN, Dhar R. Predictors of the Response to a Bolus of Conivaptan in 
Patients with Acute Hyponatremia. Abstract Supplement. Volume 13. Neurocritical Care. 2010. 
 
Rosenberg GA. Scremin O. Estrada E. Kyner WT. Arginine vasopressin V1-antagonist and atrial 
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14. Appendices 
 
-Appendix 1 – RIFLE criteria 
-Appendix 2 – modified Rankin Score 
-Appendix 3 – Apache II score system 
-Appendix 4 – Glasgow coma scale 
-Appendix 5 – ICH score criteria 
-Appendix 6 – Conivaptan monograph 

SAP_001.pdf: 
 
1 
 
 
Statistical Analysis Plan  
 
CONIVAPTAN FOR THE REDUCTION OF CEREBRAL 
EDEMA IN INTRACEREBRAL HEMORRHAGE – 
A Safety and Tolerability Study 
 
NSJC-1601 NCT03000283 
 
Funded by United Hospital Medical Education and Research Committee 
 
 
 
 
Principal Investigator: 
Jesse J. Corry, MD 
 
 
Co-Investigators: 
Ganesh Asaithambi, MD 
Arif Shaik, MD 
Jeff Lassig, MD 
 
Research Nurse: 
Amy Castle, RN 
 
Study Coordinator: 
Emily Marino, BS 
Bridget Ho, BA, CCRC 
 
 
Final document date: 4/3/2020 
 
 
 
United Hospital, part of Allina Health 
John Nasseff Neuroscience Institute, part of Allina Health 
333 North Smith Avenue 
St. Paul, MN 55102 
651-241-6550 


 
2 
 
TABLE OF CONTENTS 
Section 
Page 
1. List of Abbreviations  
3 
2. Introduction 
4 
3. Study Objectives and Endpoints 
5 
4. Investigation Plan 
6 
5. Statistical Methods 
7 
5.1: Study Subjects and Analysis Set 
7 
5.2: General Methodology 
7 
5.3: Evaluation of Objectives 
7 
5.4: Safety Evaluation 
7 
 
 
 


 
3 
 
1. List of Abbreviations  
AE – adverse event 
ALT – alanine transaminase 
AQP4 – aquaporin-4 
AST – aspartate transaminase 
AVP – arginine-vasopressin 
BSI – blood stream infection 
BWC – brain water content 
CBF – cerebral blood flow 
CE - cerebral edema 
CPP – cerebral perfusion pressure 
CSF – cerebral spinal fluid 
CT - computed tomography 
EEG – electroencephalogram 
EMR – electronic medical record 
EVD – external ventricular drain 
FWD – free-water deficits 
GCS – Glasgow coma scale 
GFR – glomerular filtration rate 
HC – hyperchloremia 
HS – hypertonic saline 
ICH – Intracerebral hemorrhage 
ICP - intracerebral pressure 
ICU – intensive care unit 
IV – intravenous 
LAR – legally authorized representative 
LOS – length-of-stay 
mRS – modified Rankin scale 
Na+ - sodium 
PEG – percutaneous endoscopic gastrostomy 
PICC – peripherally inserted central catheter 
RRT – renal replacement therapy 
SAE – serious adverse event 
TBI – traumatic brain injury 
UTI – urinary tract infection 
 
 
 
 


 
4 
 
2. Introduction 
 
Intracerebral hemorrhage (ICH) represents ~10-15% of all strokes in the United States, 
numbering 50-70,000 cases per year. Mortality and morbidity are high in ICH, with a 30-
day mortality of ~40%, and only 20% of ICH patients classified as independent at 6 
months. Only admission to a neuro-intensive care unit (ICU), and the use of a computed 
tomography (CT) scanner, have been shown to improve outcome from ICH. With 
respect to cost, ICH represents 34% of years of potential life lost to stroke.  
 
Complicating ICH is the development of cerebral edema (CE). Worsening CE has been 
implicated in delayed neurological deterioration, and worse patient outcomes, largely 
due to the elevation of intracerebral pressure (ICP). Elevations in ICP reduce the ability 
of blood to reach the brain, exacerbating the injury and producing ischemia. Reduction 
of this edema may reduce the degree of neuronal death, decreasing hospital length-of-
stay (LOS), and improving short-term outcomes.  
 
Wide variability exists in the treatment of ICP and CE among intensivists. The use of 
mannitol, which elevates the osmolarity within the cerebral vasculature, promoting water 
movement across the blood-brain barrier and into the capillary system, is common, but 
is limited by its deleterious effects on renal function, fluctuations in intravascular volume, 
and pH. Most concerning is the slow elimination of mannitol from the cerebrospinal fluid 
(CSF), which may potentially require progressively higher doses, over time to control 
ICP, and may result in rebound CE. Increasingly, hypertonic saline (HS), which acts 
similar to mannitol, is being used to abate CE. However, this therapy has not 
demonstrated any survival or outcome benefit despite reductions in ICP. A retrospective 
review of available data at Henry Ford Health System preliminarily demonstrates 
adverse effects on renal function with the use of HS. Further, anecdotal observations 
have noted changes in renal function and difficulty replacing free-water deficits (FWD) 
following aggressive antecedent use of HS. A known side-effect of HS therapy is 
hyperchloremia (HC). Chlorine is a potent renal vasoconstrictor, thus potentially 
reducing blood flow, precipitating renal ischemia, and reducing glomerular filtration rate. 
Finally, the use of HS may be associated with increased risk of blood-stream infections 
(BSI), and trends to increased risk of nosocomial and urinary tract infections (UTI).  
 
In sum, neurocritical care needs a safer alternative therapy that can reduce the 
development of CE, potentially decreasing ICU LOS and possibly improving outcomes. 
Conivaptan, a non-selective Arginine-Vasopressin (AVP) V1A/V2 antagonist, reduces the 
production of aquaporin-4 (AQP4) production, the predominant class of water channel in 
the brain, thus promoting aqueresis. Conivaptan is approved for the treatment of 
euvolemic and hypervolemic hyponatremia. This mechanism of action suggests that 
conivaptan could potentially be used clinically to reduce CE.  Current clinical data in 
traumatic brain injury (TBI) patients demonstrate conivaptan is safe and well tolerated 
using a single dose to increase sodium (Na+) in a controlled fashion to reduce ICP. 
Further, additional work has demonstrated the safety and tolerability of conivaptan in 
doses ranging from 10-80 mg/day in the neurocritical care population. Recently, 
bolusing of conivaptan (20 mg) has been shown to lower ICP in hyponatremia following 
TBI and cerebral ischemia. The authors reported improvements in cerebral perfusion 
pressure (CPP) and stable blood pressure, and a prolonged reduction in ICP. They 
theorize that the antagonism of V2 by conivaptan promotes free water loss to reduce 
brain water content (BWC), while the antagonism of V1 antagonism may improve 


 
5 
 
cerebral blood flow (CBF) and reduce blood brain barrier permeability. 
 
Given the enormous costs of ICH, problems with current therapies, and variability in 
treatment, there is an urgent need to identify a therapy that has a better safety and 
effectiveness profile than the the currently used agents. Our central hypothesis is that 
through reductions in AQP4 expression, the early use of conivaptan will reduce CE 
while also being safe in the ICH population. Our long term goal is to show that early use 
of conivaptan in ICH will reduce CE, thus improving outcomes and reducing the need 
for rescue therapies, ICU LOS, and overall treatment cost. The objective of this 
proposal is to first establish whether conivaptan use, at a dose currently determined as 
safe (40 mg/day), can reduce CE. This is an essential first step in understanding the 
role of conivaptan in CE management. If this proof-of-concept study demonstrates the 
desired effect, work can take place identifying the optimal dosing and frequency 
needed for maximal effect. 
 
 
3. Study Objectives and Endpoints 
 
Study Objectives 
The study population consists of patients with ICH at risk for developing CE. 
 
a. Primary Objective – Safety and Tolerability 
An evaluation of the safety assessment parameters of each of the seven (7) subjects will be 
done by the PI and Co-I during the patient’s care. Should events occur regarding the 
administration of conivaptan that raise safety concerns, the PI has the authority to withdraw 
the subject and/or halt the study pending further investigation. 
 
b. Secondary Objectives 
Several secondary hypotheses can be tested for data generated by this investigation: 
 
1. Reduction in CE as measured on CT. Goal is a 5-10% reduction in CE over time. 
 
2. Patient outcomes: the modified Rankin Scale (mRS) will be used to assess patient outcomes 
at hospital discharge. This scale assess functional deficits on a scale from 0 (no deficit) to 6 
(death). 
 
3. Cost of care: Several proximal measures will be used to assess cost, including length of stay 
in the ICU, the need for EVD/bolt or surgical procedures to reduce or manage CE, the need 
for lines (central venous, arterial, PICC) or tracheostomy/PEGs, and the number of patients 
that required ventilation. 
 
Study Endpoints 
 
1. Laboratory values: assessment will end at the completion of conivaptan administration 
(Day 3). 
 
2. Long-term Outcome: Patients will be observed for three months, beginning at enrollment, 
to determine long-term outcomes of conivaptan treatment. 
 
 
 


 
6 
 
4. Investigation Plan 
 
This a single-center, open-label prospective study which aims to evaluate the safety and 
tolerability of conivaptan in patients with ICH that are at risk for developing CE.  The study will 
include 7 patients with a diagnosis of ICH that is ≥ 20 cc in volume, aged between 18 – 80 
years. All patients will receive 20mg IV of conivaptan every 12 hours equaling 40mg/day over 2 
days (4 doses total), in addition to the standardized ICH management. 
 
All observations and assessments will be conducted as displayed in Table 1 of the 
Protocol. Patients will have CT scans at baseline and ~24, 72, and 168 hours (7 days) 
from enrollment to check for bleeding, lasting edema, or rebound edema. An 8 hour 
variance is permitted. It is preferable that the CT scans be done at 3mm increments as 
this is helpful for volume analysis, but 5mm is acceptable. Further imaging is left to the 
discretion of the treating/primary service physician. Electrolytes (standard-of-care, 
basic metabolic panel) for all subjects/patients will be measured every 12 hours for the 
first 72 hours of the study, and then daily after 72 hours. This is considered a regular 
schedule based on clinical need. However, during the ~48 hour period when the 
subjects are receiving conivaptan, a comprehensive metabolic panel, Mg, and PO4 will 
be drawn and analyzed 6 hours after each conivaptan dose. These labs may be done 
sooner based on the patient’s progress/need and/or the attending physician’s 
direction. Neurological exams (e.g., EEGs), vital signs, and urine output 
measurements will be conducted as per Neuro-ICU protocol. The need for ancillary 
monitoring tools (i.e. EVDs, bolts, microdialysis, EEG, near-infrared spectroscopy) will 
be at the discretion of the treating physicians. Subjects will return for a 3 month follow-
up assessment to assess neurological function and a final CT scan. 
 
Study Duration: Each subject is expected to participate in the study for 7 days 
(including medication administration and wash-out) and the 3-month follow up.  
 
Inclusion Criteria 
 
Age ≥18 years old and < 80 years. 
 
Diagnosis of primary ICH > 20 cc in volume. 
 
Enrollment within 48 hours from initial symptoms. 
 
Signed informed consent from the patient or obtained via their legally authorized 
representative (if the patient is not able to sign the informed consent 
themselves). The patient’s decisional capacity to either provide or refuse 
consent will be determined using the Glasgow Coma Scale (GCS), which is 
being assessed at baseline and at 24 hours (+/- 6hrs) after enrollment. A 
potential study participant with a GCS > 14 will be asked to provide their own 
initial study consent. A GCS ≤ 14 would indicate the need to pursue consent via 
legally authorized representative. Patient and/or LAR must be English speaking. 
 
 
Exclusion Criteria 
 
Current need for renal replacement therapy (RRT). 
 
GFR of <30 mL/minute at time of admission. 
 
Participation in another study for ICH or intraventricular hemorrhage. 
 
ICH related to infection, thrombolysis, subarachnoid hemorrhage, trauma or tumor. 
 
Presence of HIV or active fungal infection that is known based on information in the 
EMR. 


 
7 
 
 
Continued use of digoxin or amlodipine (as recommended by the 
manufacturer due to CYP3A inhibition). 
 
Active hepatic failure as defined by AST >160 units/L and/or ALT >180 
units/L, or total bilirubin levels greater than four times normal levels 
(>4.8mg/dL). 
 
Serum Na+> 145 mmol/L (admission labs or any time prior to recruitment/enrollment). 
 
Unable to receive conivaptan based on contraindications indicated by the manufacturer. 
 
Pregnant or lactating females. 
 
Not expected to survive within 48 hours of admission, or a presumed diagnosis 
of brain death. 
 
5. Statistical Methods 
 
5.1: Study Subjects and Analysis Sets 
 
All enrolled patients will be included in a single analysis set and data will be summarized using 
frequencies and percentages. 
 
 
5.2: General Methodology 
 
This study is looking to preliminarily evaluate the safety, tolerability, and efficacy of conivaptan 
treatment. Unfortunately, it is not powered to provide robust statistical evaluation of safety and 
tolerability, nor to detect differences in efficacy between subjects. As such, all analysis will be 
descriptive in nature. Categorical variables will be summarized using counts and percentages. 
Continuous variables will be summarized using descriptive statistics: number of patients, mean, 
median, and full range, as appropriate.  
 
 
Statistical analysis will consist of: 
 
Descriptive analysis of patient characteristics 
 
Frequency of relevant complications and medical interventions 
 
Changes in CE volume 
 
5.3 Evaluation of Objectives 
 
Safety and tolerability will be assessed via the number of patients that experience abnormal 
seizure activity, show abnormal laboratory values, have increased infection rates, or exhibit an 
adverse events directly related to treatment with conivaptan. The change in CE volume will be 
reported as a measure of potential efficacy, and potential impacts on cost of care will be 
assessed by the length of stay in the ICU and the use of medical interventions to reduce CE 
volumes. Patient outcomes will be assessed using the mRS at discharge. Due to the small 
number of patients in this trial and absence of a control group, all evaluation will be descriptive 
only.   
 
 
5.4 Safety Evaluation 
 
Subjects will be monitored throughout their hospital stay. Adverse events (AE) will be assessed 
in terms of their seriousness, duration, intensity, and relationship to the study drug. All 


 
8 
 
anticipated and unanticipated AE will be collected. Subjects will be able to contact the 
investigator at any time during the study. The outcome of each event, including any 
interventions used, will be observed and documented.  
 
 
a. Adverse Event Definitions and Reporting Requirements 
 
An AE is any complaint or untoward medical occurrence that is an unintended disease or injury 
or untoward clinical sign (including abnormal laboratory findings) in a subject, whether or not it is 
related to the investigational drug.  
 
A Serious Adverse Event (SAE) is an untoward medical occurrence in a subject that may or 
may not be related to the investigational drug, but that meets the criteria of “serious” by resulting 
in one of the following outcomes:  
• Death 
• Requires initial or prolonged inpatient hospitalization 
• Is life-threatening (that is, immediate risk of dying). 
• Is a persistent or significant disability/incapacity. 
• Other significant medical hazard. 
 
 
All adverse events will be collected and documented throughout the study. The PI 
will asses each AE to determine severity, relatedness to the study drug, and if it was 
anticipated or unanticipated.