Study of Stroke Related Edema Treatments

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified May 2014 by University of Florida
Sponsor:
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT01954290
First received: September 26, 2013
Last updated: May 8, 2014
Last verified: May 2014
  Purpose

Stroke remains the fourth leading cause of death in the United States (second worldwide) and a leading cause of long-term disability, resulting in total direct and indirect costs of approximately $73.7 billion annually. The failure of novel therapies in clinical trials demonstrates that the complex neural response to stroke must be targeted at multiple levels to improve patient outcomes. Despite significant improvements in stroke treatment and management, 1 year survival rate among stroke patients aged 65 years or more is around 25%, and 5- year survival rate amounts to approximately 50%. The highest chances of death are within 30 days of stroke. Mortality increases due to worsening brain dysfunction, elevated intracranial pressure (ICP), and other comorbid conditions.

Treatments aimed at reducing post-stroke cytotoxic edema may reduce the risk for development of malignant stroke and mortality. Current treatments such as osmo-therapy and hemicraniectomy have substantial limitations, and mortality remains high, despite these measures outcomes remain unsatisfactory. There is a great need for alternative medical approaches which are safe, predictable, and help to ameliorate post stroke edema.


Condition Intervention Phase
Acute Cerebrovascular Accident
Cerebral Edema
Drug: Conivaptan
Drug: Hypertonic saline
Drug: Mannitol
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment of Brain Edema and Herniation Secondary to Ischemic or Hemorrhagic Stroke

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Modified Rankin Score [ Time Frame: At the time of discharge from hospital, and 3 months after initial event ] [ Designated as safety issue: Yes ]

    The modified Rankin Scale (m-RS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people after they have suffered a stroke.It is one of the most widely used clinical outcome measure for stroke clinical trials. The score is given according to following scale.

    0- No symptoms at all

    1. No significant disability despite symptoms; able to carry out all usual duties and activities
    2. Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance
    3. Moderate disability; requiring some help, but able to walk without assistance
    4. Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance
    5. Severe disability; bedridden, incontinent and requiring constant nursing care and attention
    6. Dead

  • National Institutes of Health Stroke Severity (NIHSS) scale [ Time Frame: At the time of discharge from hospital, and 3 months after initial event ] [ Designated as safety issue: Yes ]
    NIHSS is a tool used by healthcare providers to objectively quantify the degree of impairment caused by a stroke. It is composed of 11 items. Each item scores a specific ability between a score of 0-4. Usually, for each item, a score of 0 indicates normal function in that specific ability, while a higher score indicates some level of impairment. The individual scores from each item are added together to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.

  • Neurological status of the subject [ Time Frame: At the time of discharge from hospital, and 3 months after discharge ] [ Designated as safety issue: Yes ]
    Neurological status of a stroke subject is assessed by physical neurological examination of the subject by a qualified neurologist. It is one of the most important aspect in determining neurological health of a subject after treatment for stroke. It also helps to determine stroke severity and prognosis.


Secondary Outcome Measures:
  • All cause mortality data [ Time Frame: 3 months after initial event ] [ Designated as safety issue: No ]
    Mortality data indicates the severity of stroke.


Other Outcome Measures:
  • MRI brain- findings [ Time Frame: 3 Months after Initial Event ] [ Designated as safety issue: No ]
    MRI of the Brain.


Estimated Enrollment: 80
Study Start Date: November 2014
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Hypertonic Saline (3%) and/or Mannitol arm

The subjects in this arm will be given hypertonic saline and/or Mannitol.

For hypertonic saline,various concentrations are used clinically,up to 30-mL boluses of 23.4% saline.Rapid increases in sodium in this context do not appear to cause other neurologic complications observed with rapid correction of hyponatremia.Sodium levels up to 160 mmol/L may be acceptable,beyond which it may lead to worsening delirium,seizures,and overall poor outcome.

For Mannitol,every 4 hours serum osmolarity,serum glucose,urea,sodium and potassium will be measured till the therapy is given.Major complications include hypovolemia and hypotension.Strict fluid goals and volume replacement are essential.Impaired mannitol clearance may manifest as nephrotoxicity.Common practice includes repeating measurements of serum osmolarity and withholding repeat doses of mannitol when osmolarity exceeds 320 milliosmol(mOsm).Monitoring the osmole gap may be a more sensitive method for discerning mannitol clearance.

Drug: Hypertonic saline
Hypertonic saline in the dose of 30ml/hr, with every 4 hourly measurements of serum osmolarity, serum sodium and potassium. Hypertonic saline will be increased by 30 ml to achieve target serum sodium of 150-160 and serum osmolarity 300-320
Other Names:
  • Sodium chloride injection (3% or 5%)
  • Brand name: Viaflex
Drug: Mannitol
Mannitol given at the dose of 0.5 to 1.0 gm/kg IV over 10-20 minutes. Maximum effect is seen in 20 minutes and duration of action is 4 hours. Repeat doses of 0.25 to 0.5 gm/kg Q 4-6 hours are normally frequently used.
Other Name: Brand name: Osmitrol
Experimental: Conivaptan arm
The subjects in this arm will be given infusion of Conivaptan.
Drug: Conivaptan
Intravenous conivaptan 20 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 20 mg over 24 hours (0.83 mg/hour) for 2-4 days; may increase to a maximum dose of 40 mg over 24 hours (1.7 mg/hour) if serum sodium is not rising sufficiently; total duration of therapy not to exceed 4 days.
Other Name: Vaprisol

Detailed Description:

Previous work has demonstrated the pathophysiological role of arginine-vasopressin (AVP) in ischemic stroke. The mechanism of action of AVP is by 3 receptor subtypes: V1a, V1b and V2 expressed in brain, pituitary gland, myocardium, vasculature and kidneys. The role of the vasopressin receptors V1a and or V2 subtype in cerebral edema formation after ischemic stroke remains controversial. The V1a receptor antagonism causes platelet inhibition, aquaporin-4 up regulation; reduce infarct size and vasodilation. V1 antagonists has also been shown to prevent ischemia-induced cerebral edema development, suggesting that the V1 vasopressin receptor is important in water regulation in brain cells. Another study indicated that the vasopressin receptor V1 is involved in the pathogenesis of secondary brain damage after focal cerebral ischemia. Recently, few studies have demonstrated that a V2 receptor antagonist (OPC-31260), may be one of the effective drugs for the early treatment of cytotoxic edema and brain injury. Treatment of OPC-31260 ameliorated cerebral neurological deficit in transgenic (GET-1) mice after water intoxication. Treatment of OPC-31260 also significantly abolished water accumulation and down regulated Aquaporin-4 (AQP-4) expression level in GET-1 mice after water intoxication. The intensity of AQP-4 staining was almost comparable with that of the controls without water intoxication. It was also shown that OPC-31260 at doses of 10 to 30 mg/kg produced a dose-dependent inhibition of subarachnoid hemorrhage-induced cerebral edema formation, accompanied by an increase in urinary volume and decrease in urine osmolality without a significant alteration of urine electrolytes. OPC-31260 is also effective in treating water retention diseases, such as hyponatremia caused by inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. V2 receptor antagonism will also help in abolishing water accumulation, decreased Glial Fibrillary Acidic Protein (GFAP) in astrocytes and most importantly causes renal tubule-selective diuretic effect called aquaresis (electrolyte sparing diuresis), which may have additional benefit in the reduction of cerebral edema.

This combined approach of V1a and V2 AVP receptor antagonism will lead to attenuation of ischemia related cerebral edema and infarct volume by modulating ischemia-evoked AQP-4 expression. This effect should help behavior and mortality which in turn will improve outcome in stroke patients. The purpose of this project is to test the effect of the mixed V1a and V2 receptor blockade on ischemic or hemorrhagic stroke outcome.

In summary, the investigators are using the approach of mixed vasopressin antagonism on post stroke edema, infarct volume and outcome. This research will lead to a greater understanding of the roles and interactions of the different AVP receptors and pathophysiology of post stroke cytotoxic edema. New information on the effects of mixed blockade of V1a and V2 receptors on the prevention of cytotoxic edema post stroke will be revealed.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects with age ≥18 years and ≤80 years at the time of screening.
  • Hemorrhagic stroke or large vessel ischemic stroke patients diagnosed by MRI or CT scan of Head.
  • Subjects who have presented to hospital within 24 hours of symptom onset.
  • The subject or his/ her legal representative is willing to undergo informed consent process prior to enrollment into this study.

Exclusion Criteria:

  • Subject with age < 18 years and >80 years at the time of screening.
  • Subjects with absence of stroke by imaging of brain by CT scan or MRI.
  • Lacunar stroke or small vessel stroke.
  • Time of symptom onset cannot be determined.
  • Subjects with renal or hepatic failure.
  • Subjects with hypovolemia or hypotension as determined by the study team.
  • Subjects with hypernatremia.
  • Subject who is pregnant or lactating.
  • Subject is already participating in other investigational clinical trial.
  • The subject or legal representative is unable to provide informed consent.
  • The subject is medically unstable to participate in the trial as determined by the principal investigator.
  • The subject has any end stage medical condition as determined by the principal investigator.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01954290

Contacts
Contact: Vishnumurthy Shushuthra Hedna, MD 352-273-5550 v.hedna@neurology.ufl.edu
Contact: Michael F Waters, MD 352-273-5550 mwaters@neurology.ufl.edu

Locations
United States, Florida
Shands Hospital at University of Florida
Gainesville, Florida, United States, 32610
University of Florida at Medical Plaza
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Investigators
Principal Investigator: Vishnumurthy Shushuthra Hedna, MD University of Florida
Study Director: Michael F Waters, MD University of Florida
  More Information

No publications provided

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT01954290     History of Changes
Other Study ID Numbers: Protocol-01
Study First Received: September 26, 2013
Last Updated: May 8, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Florida:
Stroke
Brain Edema
Brain Herniation
Conivaptan

Additional relevant MeSH terms:
Edema
Cerebral Infarction
Stroke
Brain Edema
Signs and Symptoms
Brain Infarction
Brain Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Mannitol
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 16, 2014