Hepatic EncephalopathyPhase 1/2NCT02048969
Treatment of Hepatic Encephalopathy With Flumazenil and Change in Cortical GABA Levels in MRS
A Phase 1/2 study testing Flumazenil in people with Hepatic Encephalopathy and Liver Cirrhosis, run by Yale University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Hepatic Encephalopathy, Liver Cirrhosis
- What is being tested?
- Flumazenil
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2014to Oct 2017
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Yale Psychological Medicine Research Center
New Haven, Connecticut, 06520
About this study
Official title: Treatment of Hepatic Encephalopathy With Benzodiazepine Antagonist (Flumazenil) and Change in Cortical GABA Levels in Localized 1H-MR Spectroscopy
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.
Read the 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.
- Conditions
- Hepatic Encephalopathy, Liver Cirrhosis
- Being tested
- Flumazenil, Placebo
- Keywords
- hepatic encephalopathy, flumazenil, liver cirrhosis
- Medical subject headings
- Hepatic Encephalopathy, Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FlumazenilDrug
Also called Romazicon
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Flumazenil | Experimental | 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. Receives: Drug: Flumazenil |
| Saline | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: one year
Secondary outcomes (2)
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.
Measured: one year
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.
Measured: one year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2014 (estimated)
- Study startJun 2014
- Primary completionOct 2017
- Study completionOct 2017
Why it stopped: No subjects were able to be recruited for the study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatic EncephalopathyStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Hochang B Lee, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02048969
- Sponsor's protocol ID
- 1311013071
- Other IDs
- P30DK034989
- Status last verified
- Jul 2020
- First submitted
- 27 Jan 2014
- Last updated
- 7 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Hepatic Encephalopathy With Benzodiazepine Antagonist (Flumazenil) and Change in Cortical GABA Levels in Localized 1H-MR Spectroscopy
- ClinicalTrials.gov ID
- NCT02048969
- Acronym / sponsor ID
- 1311013071
- Conditions
- Hepatic Encephalopathy, Liver Cirrhosis
- Keywords
- hepatic encephalopathy, flumazenil, liver cirrhosis
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: No subjects were able to be recruited for the study.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Jun 2014
- Primary completion
- Oct 2017 (actual)
- Study completion
- Oct 2017 (actual)
- First posted
- 29 Jan 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Flumazenil | Experimental | Drug: FlumazenilA 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. |
| Saline | Placebo comparator | Drug: PlaceboA 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. |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FlumazenilAlso: RomaziconA 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. | Drug | Flumazenil |
| PlaceboA 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 | Saline |
Primary outcome
hepatic encephalopathy symptoms
Time frame: one year
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.
2 secondary outcomes
hepatic encephalopathy symptoms
Time frame: one year
flumazenil impact on functional MRI
Time frame: one year
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jul 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hochang B Lee, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Flumazenil in people with Hepatic Encephalopathy and Liver Cirrhosis, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 7 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
hepatic encephalopathy symptoms (time frame: one year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jul 2020.