Conivaptan for the Reduction of Cerebral Edema in Intracerebral Hemorrhage- A Safety and Tolerability Study

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.

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 provide their own initial study consent. A GCS ≤ 14 would indicate
the need to pursue consent via legally authorized representative.

Exclusion Criteria:

1. Current need for renal replacement therapy (RRT).

2. Glomerular filtration rate (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
electronic medical record (EMR).

6. Continued use of digoxin or amlodipine (as recommended by the manufacturer due to
cytochrome P450 3A4 "CYP3A" inhibition).

7. Active hepatic failure as defined by aspartate aminotransferase (AST) >160 units/L
and/or alanine transaminase (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.