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Characterization of [11C]Flumazenil to Image GABA Transmission in Healthy Adult Subjects and Subjects With Alcohol Dependence

Primary Purpose

Alcoholism

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

[11C]flumazenil

Tiagabine

About this trial

This is an interventional basic science trial for Alcoholism

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Healthy Control Subjects:

Males or Females 18-45
Absence of present or past psychiatric conditions (including alcohol or drug dependence)
A negative urine drug screen
Medically Healthy

Subjects with alcohol dependence:

Males or Females 18-45
Fulfill DSM-IV Diagnosis for Alcohol Dependence
Negative Urine Drug Screen
Negative Urine ETG/ETS
Medically Healthy
Abstinent from alcohol for a minimum of 1 month prior to scanning procedures

Exclusion Criteria:

Healthy Control Subjects:

Pregnancy or lactation, lack of effective birth control during 15 days before the scans
Presence or positive history of serious medical or neurological illness, including low hemoglobin.
Any use (within recent past 6 weeks) of amphetamines, opiates, cocaine, ecstasy PCP.
Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan (but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant. Dental fillings do not present a risk for MRI), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists.
Currently employed as radiation worker; or participation in radioactive drug research protocols within the previous year such that the total cumulative annual radiation dose (i.e., from participation in the previous research studies and this study) would exceed the radiation dose limits specified in the FDA regulations at 21 CFR 361.1, Radioactive Drugs Considered Generally Safe and Effective (i.e. annual cumulative radiation dose limit = 5 rems to gonads, blood-forming organs, lens of eye, whole body; 15 rems to other organs).
Subjects with known hypersensitivity to flumazenil or benzodiazepines; subjects who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus or in patient who are showing signs of serious cyclic antidepressant overdose)

Subjects with alcohol dependence:

Pregnancy or lactation, lack of effective birth control during 15 days before the scans
Presence or positive history of serious medical or neurological illness or any cardiovascular disease, low hemoglobin
Any other current major axis I psychiatric diagnosis except alcohol dependence (subjects with nicotine dependence will not be excluded)
Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan (but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant. Dental fillings do not present a risk for MRI), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists.
Currently employed as radiation worker; or participation in radioactive drug research protocols within the previous year such that the total cumulative annual radiation dose (i.e., from participation in the previous research studies and this study) would exceed the radiation dose limits specified in the FDA regulations at 21 CFR 361.1, Radioactive Drugs Considered Generally Safe and Effective (i.e. annual cumulative radiation dose limit = 5 rems to gonads, blood-forming organs, lens of eye, whole body; 15 rems to other organs).
Subjects with known hypersensitivity to flumazenil or benzodiazepines; subjects who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus or in patient who are showing signs of serious cyclic antidepressant overdose)

Sites / Locations

University of Pittsburgh

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PET scans

Arm Description

Both alcoholics and healthy controls will undergo two [11C]flumazenil PET scans: one at baseline and one post administration of 0.2 mg/kg Tiagabine.

Outcomes

Primary Outcome Measures

To measure changes in [11C]flumazenil binding in the brain using PET scans

Tiagabine induced change in [C-11]flumazenil distribution volume (VT)

Refer to for consensus nomenclature J Cereb Blood Flow Metab. 2007 Sep;27(9):1533-9. Epub 2007 May 9.

Secondary Outcome Measures

Full Information

NCT ID

NCT01904487

First Posted

July 16, 2013

Last Updated

August 25, 2017

Sponsor

Rajesh Narendran

1. Study Identification

Unique Protocol Identification Number

NCT01904487

Brief Title

Characterization of [11C]Flumazenil to Image GABA Transmission in Healthy Adult Subjects and Subjects With Alcohol Dependence

Official Title

Characterization of [11C]Flumazenil to Image GABA Transmission in Healthy Adult Subjects and Subjects With Alcohol Dependence

Study Type

Interventional

2. Study Status

Record Verification Date

August 2017

Overall Recruitment Status

Completed

Study Start Date

April 19, 2011 (undefined)

Primary Completion Date

October 1, 2013 (Actual)

Study Completion Date

October 1, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Rajesh Narendran

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Background: - This study is being done to examine the role of a chemical GABA in the brain of alcohol dependent patients. GABA is the chief inhibitory neurotransmitter in the central nervous system. It helps induce relaxation and sleep and balances the brain by inhibiting over-excitation. Several studies have reported that anxiety disorders such as panic attacks, seizure disorders, and numerous other conditions including addiction, are all related to low GABA activity. Therefore, we will examine differences in GABA levels between healthy controls and subjects with alcohol addiction. Studies such as this are important to the understanding of the role of GABA in alcohol addiction.

Detailed Description

Objectives: - By comparing the two PET scans (before and after tiagabine) done in the same day, we can understand more about how much GABA your brain makes and about the activity of your GABA receptors in the brain. Eligibility: - Individuals 18-45 years of age who are heavy drinkers or healthy controls. Design: Procedures to determine if you are eligible to take part in a research study are called "screening procedures". This will require you to come to the investigators office for approximately ½ day. For this research study, the screening procedures include comprehensive psychiatric and medical evaluations. Participants be asked to abstain from drugs and alcohol for the duration of the study and will be required to make trips several times a week for two weeks to provide clean urine samples. During one of the visits prior to the PET scans, participants will have a magnetic resonance image (MRI) taken of their brain. We will be using a technology called Positron Emission Tomography (PET), which is a method used to take pictures of the body, in this case, the brain. We will be injecting you with a radiotracer called [11C]flumazenil. A radiotracer is a small amount of a drug with radioactivity attached. Because the radiotracer temporarily sticks to the GABA receptors in the brain, the PET scan can then measure the activity at GABA receptors by measuring the amount of the radiotracer. You will undergo two PET scans with [11C]flumazenil on one day for this study. After the first PET scan, you will be given an oral dose of tiagabine (Gabitril®), which is a medication approved for the treatment of seizure disorder. Tiagabine raises levels of GABA in the brain. It is used in this study so that we can measure the changes in GABA levels. Blood samples will be drawn during the PET scans.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alcoholism

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

PET scans

Arm Type

Experimental

Arm Description

Both alcoholics and healthy controls will undergo two [11C]flumazenil PET scans: one at baseline and one post administration of 0.2 mg/kg Tiagabine.

Intervention Type

Radiation

Intervention Name(s)

[11C]flumazenil

Intervention Description

[11C]flumazenil is a radiotracer used to measure levels of the neurotransmitter GABA in the human brain.

Intervention Type

Drug

Intervention Name(s)

Tiagabine

Intervention Description

Tiagabine raises levels of GABA in the brain. It is used in this study so that we can measure the changes in GABA levels.

Primary Outcome Measure Information:

Title

To measure changes in [11C]flumazenil binding in the brain using PET scans

Time Frame

Day 1: baseline PET scan and a follow-up PET scan 0.5 hours post administration of Tiagabine

Title

Tiagabine induced change in [C-11]flumazenil distribution volume (VT)

Description

Refer to for consensus nomenclature J Cereb Blood Flow Metab. 2007 Sep;27(9):1533-9. Epub 2007 May 9.

Time Frame

1 hour

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Healthy Control Subjects: Males or Females 18-45 Absence of present or past psychiatric conditions (including alcohol or drug dependence) A negative urine drug screen Medically Healthy Subjects with alcohol dependence: Males or Females 18-45 Fulfill DSM-IV Diagnosis for Alcohol Dependence Negative Urine Drug Screen Negative Urine ETG/ETS Medically Healthy Abstinent from alcohol for a minimum of 1 month prior to scanning procedures Exclusion Criteria: Healthy Control Subjects: Pregnancy or lactation, lack of effective birth control during 15 days before the scans Presence or positive history of serious medical or neurological illness, including low hemoglobin. Any use (within recent past 6 weeks) of amphetamines, opiates, cocaine, ecstasy PCP. Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan (but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant. Dental fillings do not present a risk for MRI), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists. Currently employed as radiation worker; or participation in radioactive drug research protocols within the previous year such that the total cumulative annual radiation dose (i.e., from participation in the previous research studies and this study) would exceed the radiation dose limits specified in the FDA regulations at 21 CFR 361.1, Radioactive Drugs Considered Generally Safe and Effective (i.e. annual cumulative radiation dose limit = 5 rems to gonads, blood-forming organs, lens of eye, whole body; 15 rems to other organs). Subjects with known hypersensitivity to flumazenil or benzodiazepines; subjects who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus or in patient who are showing signs of serious cyclic antidepressant overdose) Subjects with alcohol dependence: Pregnancy or lactation, lack of effective birth control during 15 days before the scans Presence or positive history of serious medical or neurological illness or any cardiovascular disease, low hemoglobin Any other current major axis I psychiatric diagnosis except alcohol dependence (subjects with nicotine dependence will not be excluded) Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan (but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant. Dental fillings do not present a risk for MRI), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists. Currently employed as radiation worker; or participation in radioactive drug research protocols within the previous year such that the total cumulative annual radiation dose (i.e., from participation in the previous research studies and this study) would exceed the radiation dose limits specified in the FDA regulations at 21 CFR 361.1, Radioactive Drugs Considered Generally Safe and Effective (i.e. annual cumulative radiation dose limit = 5 rems to gonads, blood-forming organs, lens of eye, whole body; 15 rems to other organs). Subjects with known hypersensitivity to flumazenil or benzodiazepines; subjects who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus or in patient who are showing signs of serious cyclic antidepressant overdose)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rajesh Narendran, MD

Organizational Affiliation

University of Pittsburgh

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

15864554

Citation

Lingford-Hughes AR, Wilson SJ, Cunningham VJ, Feeney A, Stevenson B, Brooks DJ, Nutt DJ. GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study. Psychopharmacology (Berl). 2005 Aug;180(4):595-606. doi: 10.1007/s00213-005-2271-x. Epub 2005 Apr 28.

Results Reference

background

PubMed Identifier

8947325

Citation

Gilman S, Adams KM, Johnson-Greene D, Koeppe RA, Junck L, Kluin KJ, Martorello S, Heumann M, Hill E. Effects of disulfiram on positron emission tomography and neuropsychological studies in severe chronic alcoholism. Alcohol Clin Exp Res. 1996 Nov;20(8):1456-61. doi: 10.1111/j.1530-0277.1996.tb01149.x.

Results Reference

background

PubMed Identifier

8032146

Citation

Farde L, Pauli S, Litton JE, Halldin C, Neiman J, Sedvall G. PET-determination of benzodiazepine receptor binding in studies on alcoholism. EXS. 1994;71:143-53. doi: 10.1007/978-3-0348-7330-7_15.

Results Reference

background

PubMed Identifier

8390063

Citation

Litton JE, Neiman J, Pauli S, Farde L, Hindmarsh T, Halldin C, Sedvall G. PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls. Psychiatry Res. 1993 Apr;50(1):1-13. doi: 10.1016/0925-4927(93)90019-e.

Results Reference

background

Links:

URL

http://www.addictionstudies.pitt.edu/

Description

Psychiatric Molecular Imaging Program Addiction Website

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Characterization of [11C]Flumazenil to Image GABA Transmission in Healthy Adult Subjects and Subjects With Alcohol Dependence

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