Conivaptan for the Reduction of Cerebral Edema in Intracerebral Hemorrhage- A Safety and Tolerability Study
Condition: Cerebral Hemorrhage; Cerebral Edema; Intracerebral Hemorrhage; Stroke
MeSH terms: Cerebral Hemorrhage; Brain Edema; Hemorrhage; Edema
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Conivaptan
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Vaprisol
Intervention MeSH terms: Conivaptan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Conivaptan