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

Primary Purpose

Hepatic Encephalopathy, Liver Cirrhosis

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Flumazenil
Placebo
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Hepatic Encephalopathy focused on measuring hepatic encephalopathy, flumazenil, liver cirrhosis

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Yale Psychological Medicine Research Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Flumazenil

Saline

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

hepatic encephalopathy symptoms
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
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
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.

Full Information

First Posted
January 27, 2014
Last Updated
July 3, 2020
Sponsor
Yale University
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT02048969
Brief Title
Treatment of Hepatic Encephalopathy With Flumazenil and Change in Cortical GABA Levels in MRS
Official Title
Treatment of Hepatic Encephalopathy With Benzodiazepine Antagonist (Flumazenil) and Change in Cortical GABA Levels in Localized 1H-MR Spectroscopy
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Withdrawn
Why Stopped
No subjects were able to be recruited for the study.
Study Start Date
June 2014 (undefined)
Primary Completion Date
October 2017 (Actual)
Study Completion Date
October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Encephalopathy, Liver Cirrhosis
Keywords
hepatic encephalopathy, flumazenil, liver cirrhosis

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Flumazenil
Arm Type
Experimental
Arm Description
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.
Arm Title
Saline
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Flumazenil
Other Intervention Name(s)
Romazicon
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
hepatic encephalopathy symptoms
Description
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.
Time Frame
one year
Secondary Outcome Measure Information:
Title
hepatic encephalopathy symptoms
Description
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.
Time Frame
one year
Title
flumazenil impact on functional MRI
Description
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.
Time Frame
one year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age: 18 and older ICD-9 diagnosis of hepatic encephalopathy Ability to feel comfortable in confined areas (like MRI) Ability to provide informed consent Speaks fluent English without any communication barriers Reliable family member or friend able to stay with participant during abstinence from HE medication prior to visit. Exclusion Criteria: Current DSM-IV-R diagnosis of Alcohol or Other Drug Abuse or Dependence Positive screen for alcohol abuse as determined by the CAGE questionnaire Positive urine toxicity screen for benzodiazepine medications or illicit drugs History of long-term use of benzodiazepine medications Current use of non-benzodiazepine agonist medications History of Panic Disorder History of any Psychotic Disorder History of seizures and/or Seizure Disorder History of dysrhythmia, cardiovascular collapse, or recent head trauma History of side effects from anticholinergic medications History of cyclic antidepressant overdose or poisoning Pregnant or nursing Resides in nursing home or other long-term care facility
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hochang B Lee, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale Psychological Medicine Research Center
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States

12. IPD Sharing Statement

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

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