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

Enrolling by invitation

Phase N/A Results N/A

Trial Description

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.

Conditions

Interventions

  • Conivaptan Drug
    Other Names: Vaprisol
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Conivaptan Treatment Group
    Description: All seven patients in this arm will receive conivaptan as described in Interventions.

Outcomes

Type Measure Time Frame Safety Issue
Primary Patient tolerance of conivaptan Baseline to 168 hours post-enrollment
Secondary In-hospital mortality Enrollment through hospital discharge, up to 3 weeks
Secondary Reduction in cerebral edema Baseline to 168 hours post-enrollment
Secondary Cost Enrollment through hospital discharge, up to 3 weeks
Secondary Modified Rankin Scale (mRS) score At discharge from ICU and from hospital, up to 3 weeks

Sponsors