Treatment of Hepatic Encephalopathy With Flumazenil and Change in Cortical GABA Levels in MRS

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified January 2014 by Yale University
Sponsor:
Information provided by (Responsible Party):
Yale University
ClinicalTrials.gov Identifier:
NCT02048969
First received: January 27, 2014
Last updated: January 30, 2014
Last verified: January 2014
  Purpose

The purpose of this study is to test feasibility of measuring flumazenil-induced changes in cortical GABA levels observed with localized 1H-MRS in relation to changes in severity of hepatic encephalopathy (HE) in subjects with non-alcoholic liver cirrhosis. This study is a double-blind, placebo-controlled, randomized, cross-over design.


Condition Intervention Phase
Hepatic Encephalopathy
Liver Cirrhosis
Drug: Flumazenil
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Treatment of Hepatic Encephalopathy With Benzodiazepine Antagonist (Flumazenil) and Change in Cortical GABA Levels in Localized 1H-MR Spectroscopy

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • hepatic encephalopathy symptoms [ Time Frame: one year ] [ Designated as safety issue: No ]
    To assess flumazenil-induced changes in cortical GABA levels, observed with localized proton magnetic resonance spectroscopy (1H-MRS) using a 4-Tesla imaging spectrometer in relation to changes in hepatic encephalopathy. MRS is a non-invasive imaging technique that allows examination of metabolic changes and biochemical information about the target brain tissues without the need for a biopsy. Hepatic encephalopathy will be measured using neuropsychological tests. These tests include Benton scoring, Hopkins Verbal Learning Test trials and delayed recall and recognition trials, Smith symbol digits, simple auditory sustained attention continuous performance test, digit span sequencing, Wechsler Adult Intelligence Scale-III symbol search, cancellation tasks, line orientation, serial 3s subtraction, Hooper visual orientation test, Trail Making Tests A & B, and orientation retest. Variables will be transformed so that higher scores indicate better cognitive function.


Secondary Outcome Measures:
  • hepatic encephalopathy symptoms [ Time Frame: one year ] [ Designated as safety issue: No ]
    To examine whether flumazenil-induced changes in cortical GABA levels (mmol/kg) observed with localized (1H-MRS) are associated with improvement in hepatic encephalopathy (HE) symptoms (when compared to HE symptoms measured when receiving placebo). Hepatic encephalopathy will be measured using a weighted battery of neuropsychological tests (z-score across variables). These tests include Benton scoring, Hopkins Verbal Learning Test trials and delayed recall and recognition trials, Smith symbol digits, simple auditory sustained attention continuous performance test, digit span sequencing, Wechsler Adult Intelligence Scale-III symbol search, cancellation tasks, line orientation, serial 3s subtraction, Hooper visual orientation test, Trail Making Tests A & B, and orientation retest. Score range is dependent on variability within the sample & treatment efficacy; however, variables will be transformed so that higher scores indicate better cognitive function.

  • flumazenil impact on functional MRI [ Time Frame: one year ] [ Designated as safety issue: No ]
    To examine the impact of flumazenil on functional MRI (fMRI). fMRI is a non-invasive technique for measuring neural activity by detecting changes in blood flow to different parts of the brain.


Estimated Enrollment: 10
Study Start Date: February 2014
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Flumazenil
A priming dose bolus of 0.4 mg of flumazenil will be administered intravenously (Minute 0). At this time the 1H-MRS scan will begin. Over the next 6 minutes, a drip infusion of flumazenil will be administered to the patient at a rate of 0.1 mg flumazenil per minute for a total of 7 doses during the scan. Total dose will be 1.0 mg.
Drug: Flumazenil
A priming dose bolus of 0.4 mg of flumazenil will be administered intravenously (Minute 0). At this time the 1H-MRS scan will begin. Over the next 6 minutes, a drip infusion of placebo mixed with saline will be administered to the patient at a rate of 0.1 mg per minute for a total of 7 doses during the scan. Total dose will be 1.0 mg.
Other Name: Romazicon
Placebo Comparator: Saline
A priming dose bolus of 0.4 mg of placebo will be administered intravenously (Minute 0). At this time the 1H-MRS scan will begin. Over the next 6 minutes, a drip infusion of placebo mixed with saline will be administered to the patient at a rate of 0.1 mg per minute for a total of 7 doses during the scan. Total dose will be 1.0 mg.
Drug: Placebo
A priming dose bolus of 0.4 mg of placebo will be administered intravenously (Minute 0). At this time the 1H-MRS scan will begin. Over the next 6 minutes, a drip infusion of placebo mixed with saline will be administered to the patient at a rate of 0.1 mg per minute for a total of 7 doses during the scan. Total dose will be 1.0 mg.

Detailed Description:

Subjects will be referred to the PI by the Yale Liver Center. If interested in participating, they will be contacted by a research assistant for an initial phone screening. If the subject passes the screening, an appointment will be made for a MRS and fMRI at the Yale Magnetic Resonance Research Center (MRRC). Subjects will be asked to abstain from their HE medication (e.g. lactulose and/or rifaximin) for 12 hours prior to their appointment. At their appointment for MRS/fMRI, they will receive two IVs, one for medication infusion and another for periodic blood draws during the MRS. Subjects will be blindly randomized to one of two groups: A or B. Group A will receive flumazenil (Romazicon) and Group B will receive placebo (saline). One week post-infusion, patients will crossover groups; those originally in Group A will crossover to Group B and those originally in Group B will crossover to Group A. Once ready, a priming dose bolus of 0.4 mg of either flumazenil or placebo will be administered intravenously (Minute 0). At this time the 1H-MRS scan will begin. Over the next 6 minutes, a drip infusion of flumazenil or placebo mixed with saline will be administered to the patient at a rate of 0.1 mg flumazenil or placebo per minute for a total of 7 doses during the scan. A baseline pharmacokinetics (PK) sample will be drawn, processed and frozen and the intravenous line used to draw the sample will remain in patient until all samples have been drawn. Seven additional PK samples (2-4 mL each) collected during and after the scan will be used to evaluate the level of flumazenil circulating throughout the bloodstream during the course of the infusion and during the washout period.

Following the MRS and fMRI, subjects will undergo a 40-minute neuropsychologic battery. Other testing procedures include liver function and drug testing. All procedures will repeat one week later with placebo or flumazenil infusion (based on the group to which he/she has been randomized). A follow-up phone call to assess for adverse events will take place in week 3.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age: 18 and older
  2. ICD-9 diagnosis of hepatic encephalopathy
  3. Ability to feel comfortable in confined areas (like MRI)
  4. Ability to provide informed consent
  5. Speaks fluent English without any communication barriers
  6. Reliable family member or friend able to stay with participant during abstinence from HE medication prior to visit.

Exclusion Criteria:

  1. Current DSM-IV-R diagnosis of Alcohol or Other Drug Abuse or Dependence
  2. Positive screen for alcohol abuse as determined by the CAGE questionnaire
  3. Positive urine toxicity screen for benzodiazepine medications or illicit drugs
  4. History of long-term use of benzodiazepine medications
  5. Current use of non-benzodiazepine agonist medications
  6. History of Panic Disorder
  7. History of any Psychotic Disorder
  8. History of seizures and/or Seizure Disorder
  9. History of dysrhythmia, cardiovascular collapse, or recent head trauma
  10. History of side effects from anticholinergic medications
  11. History of cyclic antidepressant overdose or poisoning
  12. Pregnant or nursing
  13. Resides in nursing home or other long-term care facility
  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: NCT02048969

Contacts
Contact: Deanna Martin, MPH 203-737-6309 deanna.martin@yale.edu
Contact: Amanda Brennan, MSW 203-737-6306 amanda.brennan@yale.edu

Locations
United States, Connecticut
Yale Psychological Medicine Research Center Not yet recruiting
New Haven, Connecticut, United States, 06520
Principal Investigator: Hochang B Lee, MD         
Sponsors and Collaborators
Yale University
Investigators
Principal Investigator: Hochang B Lee, MD Yale University
  More Information

No publications provided

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02048969     History of Changes
Other Study ID Numbers: P30DK34989, 1311013071
Study First Received: January 27, 2014
Last Updated: January 30, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by Yale University:
hepatic encephalopathy
flumazenil
liver cirrhosis

Additional relevant MeSH terms:
Hepatic Encephalopathy
Brain Diseases
Liver Cirrhosis
Central Nervous System Diseases
Nervous System Diseases
Liver Diseases
Digestive System Diseases
Liver Failure
Hepatic Insufficiency
Brain Diseases, Metabolic
Metabolic Diseases
Flumazenil
Antidotes
Protective Agents
Physiological Effects of Drugs
Pharmacologic Actions
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014