CTNA: Functional Neuroimaging of Alcoholism Vulnerability (PIT)

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01585168
• Collaborator: (none)
• Enrollment: 71
• Location: 1
• Arms: 4
• Duration (Months): 53
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This project compares Family History Positive (FHP) for alcoholism subjects to matched Family History Negative (FHN) subjects derived from the project Principal Investigator's National Institute on Alcohol Abuse and Alcoholism-funded longitudinal study of drinking behavior in a 2000 college freshman population (known as the Brain and Alcohol Research in College Students study (BARCS)). The age of these subjects is a valuable one at which to capture the transition from harmful use to abuse/dependence. This project explores the effects of memantine in a double-blind, randomized, counterbalanced manner on alcoholism risk-relevant tasks. More specifically, this project studies functional MRI tasks related to different aspects of reward and/or impulsivity-related behavior in different contexts, compares the underlying neural circuitry across tasks, and uses a pharmacologic probe of the glutamatergic system to examine NMDA/DA interactions. The combined measures provide the opportunity to advance our understanding of specific aspects of brain function related to familial alcoholism vulnerability in an already well-characterized population as some members evolve into alcohol abuse. In addition to conventional within-task analyses, functional network connectivity and allied approaches will be used to examine brain networks across tasks.

The investigators will study adult male and female subjects in equal numbers who are either offspring of an alcoholic parent or are FHN matched controls. The investigators will recruit and assess a total of 84 (42 FHP and 42 matched FHN) subjects between the ages of 18-21 years on initial BARCS contact. The investigators will use 4 cognitive tasks during the functional MRI (fMRI) which include: 1) a Monetary Incentive Delay Task that distinguishes networks engaged in motivational (anticipation) and consummatory (outcome) components of reward processing; 2) a Go/No-Go Task that measures the ability to inhibit response to a pre-potent stimulus; 3) an Alcohol Cue Reactivity Task that examines Nucleus Accumbens response to alcohol-related versus matched soft drink stimuli; and 4) a Pavlovian-to-Instrumental Transfer (PIT) Task that dissects a component of the Monetary Incentive Delay (MID) Task, and provides an imaging assay of a transfer-like process that can be related to real-world drinking behavior, thus informing upon and extending the key findings from CTNA-2.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Memantine; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: All subjects received both the study drug and placebo. Family history was the main variable of interest, and randomization was stratified by this variable.All subjects received both the study drug and placebo. Family history was the main variable of interest, and randomization was stratified by this variable.
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Functional Neuroimaging of Alcoholism Vulnerability: Glutamate, Reward, Impulsivity and Pavlovian-to-Instrumental Transfer (PIT)
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Family history positive, Memantine first, then placebo Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.	Drug: Memantine; Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.; Drug: Placebo; Identically appearing sugar pill, given orally
Placebo Comparator: Family history positive, placebo first, then Memantine Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.	Drug: Memantine; Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.; Drug: Placebo; Identically appearing sugar pill, given orally
Experimental: Family history negative, Memantine first, then placebo Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.	Drug: Memantine; Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.; Drug: Placebo; Identically appearing sugar pill, given orally
Placebo Comparator: Family history negative, placebo first, then Memantine Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.	Drug: Memantine; Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.; Drug: Placebo; Identically appearing sugar pill, given orally

Outcome Measures

Primary Outcome Measures

1. Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During "Win" Monetary Incentive Delay (MID) Task Between Placebo and Study Medication [4 hours post intervention on each study day, separated by 1 week to 1 month]

   All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner.

2. Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During "Loss" Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication [4 hours post intervention on each study day, separated by 1 week to 1 month]

   All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner.

Secondary Outcome Measures

1. Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication [3 hours post intervention on each study day, separated by 1 week to 1 month]

   All participants completed the BART task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. BART is a computer decision-making task that measures risk taking. Participants are presented with a series of "balloons." The object is to earn as much money as possible by pumping the balloon without popping it. The point of explosion varies from trial to trial and costs participants the money they have earned in that trial.

2. Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication [3 hours post intervention on each study day, separated by 1 week to 1 month]

   All participants completed the EDT task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. EDT is a delay-discounting task that exposes participants to choice consequences during test administration. The EDT involves multiple blocks of choices, one for each delay. Choices are made between a standard amount that is delivered immediately and is certain and a probable amount that is delayed and uncertain.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Biological father with a history of Alcoholism

• A least 1 other first- or second-degree relative with a history of Alcoholism.

Exclusion Criteria:

• Cannot be an only child

• A diagnosis of DSM-IV-TR Axis I psychotic disorders screened with the Mini International Neuropsychiatric Interview (MINI), done in the BARCS study (with the exception of Alcohol Abuse)

• Report of psychotic disorder in a 1º relative

• Prenatal exposure to alcohol (mother reported to drink 3 or more drinks on an occasion or more than 3 times per month during pregnancy

• Not speaking English fluently or being a non-native English speaker, or being educated in a primary language other than English >grade 1

• Mental retardation (Full Scale IQ<70)

• Traumatic brain injury with loss of consciousness > 30 minutes or concussion in last 30 days

• Presence or history of any medical/neurologic illness that may affect brain physiology (e.g., epilepsy, Multiple Sclerosis), including focal brain lesion seen on structural MRI (all structural scans are read by a licensed radiologist)

• Current pregnancy (all females will be tested with urine screens on the day of MRI)

• Any positive alcohol screen will result in exclusion

• Inability to comprehend the consent form appropriately

• Other specific fMRI exclusions include metal devices, clips or fragments in body (orbital x-ray performed if needed)

• Female participants under 125 pounds will be excluded from participating due to the strength and side effects in this segment of the population.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Olin Neuropsychiatry Research Center at the Institute of Living, Hartford Hospital	Hartford	Connecticut	United States	06106

Sponsors and Collaborators

• Yale University

Investigators

• Principal Investigator: Godfrey D Pearlson, MD, Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT01585168
• Other Study ID Numbers: 1106008650
• First Posted: Apr 25, 2012
• Last Update Posted: Mar 16, 2021
• Last Verified: Feb 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Yale University: Reward Circuitry; Impulsivity; Family History of Alcoholism; NMDA/DA Interactions
• Additional relevant MeSH terms: Alcoholism; Memantine

Study Results

Participant Flow

Recruitment Details	82 participants were screened for eligibility and then were consented at the Olin Research Center. However, after consent and prior to group randomization, 11 participants were excluded from the study due to follow-up eligibility paperwork (i.e. psychiatric interview, family history review, etc.) for a total of 71 randomized.

Arm/Group Title	Family History Negative (FHN): Memantine, Then Placebo	Family History Negative (FHN): Placebo, Then Memantine	Family History Positive (FHP): Memantine, Then Placebo	Family History Positive (FHP): Placebo, Then Memantine
Arm/Group Description	Participants received 2-20mg tablets of Memantine on the morning of the first study visit, then received 2 matching placebo tablets on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Participants received 2 matching placebo tablets on the morning of the first study visit, then received 2-20mg tablets of Memantine on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Participants received 2-20mg tablets of Memantine on the morning of the first study visit, then received 2 matching placebo tablets on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.	Participants received 2 matching placebo tablets on the morning of the first study visit, then received 2-20mg tablets of Memantine on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.
Period Title: Overall Study
STARTED	18	18	16	19
COMPLETED	15	17	15	18
NOT COMPLETED	3	1	1	1

Baseline Characteristics

Arm/Group Title	Family History Positive (FHP)	Family History Negative (FHN)	Total
Arm/Group Description	People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.	People who have no affected first- or second-degree relatives.	Total of all reporting groups
Overall Participants	35	36	71
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	35 100%	36 100%	71 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	24.70	22.09	23.42
Sex: Female, Male (Count of Participants)
Female	28 80%	20 55.6%	48 67.6%
Male	5 14.3%	12 33.3%	17 23.9%
Region of Enrollment (participants) [Number]
United States	33 94.3%	32 88.9%	65 91.5%

Outcome Measures

1. Primary Outcome

Title	Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During "Win" Monetary Incentive Delay (MID) Task Between Placebo and Study Medication
Description	All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner.
Time Frame	4 hours post intervention on each study day, separated by 1 week to 1 month

Outcome Measure Data

Analysis Population Description

The number of subjects analyzed differs from the overall number of subjects because analyses for this measure occurred about 48 months into recruitment.

Arm/Group Title	FHN - Memantine	FHN - Placebo	FHP - Memantine	FHP - Placebo
Arm/Group Description	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.
Measure Participants	27	27	12	12
Mean (Standard Deviation) [voxel wise BOLD signal]	-0.6994 (3.8049)	1.7115 (3.9355)	0.3683 (3.9475)	4.0298 (5.6935)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FHN - Memantine, FHN - Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments	P value was adjusted for multiple comparisons using FWE (family wise error) correction.
	Method	t-test, 2 sided
	Comments	A Paired t-test was performed to explore the difference between two groups.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.4109
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	FHN was found to have lower mean BOLD activation while given drug compared to placebo in amygdala.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FHP - Memantine, FHP - Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.125
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	3.6615
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication
Description	All participants completed the BART task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. BART is a computer decision-making task that measures risk taking. Participants are presented with a series of "balloons." The object is to earn as much money as possible by pumping the balloon without popping it. The point of explosion varies from trial to trial and costs participants the money they have earned in that trial.
Time Frame	3 hours post intervention on each study day, separated by 1 week to 1 month

Outcome Measure Data

Analysis Population Description

Participants with a family history of alcoholism (family history positive) and without a history of alcoholism (family history negative) who completed BART task.

Arm/Group Title	FHN - Memantine	FHN - Placebo	FHP - Memantine	FHP - Placebo
Arm/Group Description	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.
Measure Participants	18	19	19	26
Mean (Standard Deviation) [total pumps]	-0.12839 (1.001)	-0.04331 (1.033)	0.2727 (0.910)	-0.0789 (1.022)

3. Secondary Outcome

Title	Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication
Description	All participants completed the EDT task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. EDT is a delay-discounting task that exposes participants to choice consequences during test administration. The EDT involves multiple blocks of choices, one for each delay. Choices are made between a standard amount that is delivered immediately and is certain and a probable amount that is delayed and uncertain.
Time Frame	3 hours post intervention on each study day, separated by 1 week to 1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FHN - Memantine	FHN - Placebo	FHP - Memantine	FHP - Placebo
Arm/Group Description	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.
Measure Participants	32	32	33	33
# of times "delayed" pressed in Delay Condition	13.58831 (6.838454)	14.13 (7.414)	15.41029 (8.256729)	13.64 (7.504)
# of times "immediate" pressed in Delay Condition	10.85871 (6.972910)	11.84 (7.133)	10.34057 (5.995089)	10.22 (5.873)
# of times "delayed" pressed in Immediate Cond.	11.44094 (3.890267)	11.94 (4.096)	11.77072 (4.882568)	11.50 (4.159)
# of times "immediate" pressed in Immediate Cond.	18.57818 (12.316437)	17.74 (10.847)	14.82459 (9.884165)	14.39 (10.431)

4. Primary Outcome

Title	Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During "Loss" Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication
Description	All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner.
Time Frame	4 hours post intervention on each study day, separated by 1 week to 1 month

Outcome Measure Data

Analysis Population Description

The number of subjects analyzed differs from the overall number of subjects because analyses for this measure occurred about 48 months into recruitment.

Arm/Group Title	FHN - Memantine	FHN - Placebo	FHP - Memantine	FHP - Placebo
Arm/Group Description	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Negative (FHN): People who have no affected first- or second-degree relatives.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.	Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.
Measure Participants	27	27	12	12
Mean (Standard Deviation) [voxel wise BOLD signal]	-0.5980 (2.9465)	1.2368 (2.8177)	.7498 (3.1314)	3.4762 (2.3169)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FHP - Memantine, FHP - Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.356
	Comments	P value was adjusted for multiple comparisons using FWE (family wise error) correction.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.7264
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	FHP was found to have lower mean BOLD activation while given drug compared to placebo in anterior cingulate cortex.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FHN - Memantine, FHN - Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	1.8348
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	AE data were collected over the duration of the study (4 years).
Adverse Event Reporting Description	All AE information that were collected were expected side effects of the study medication.
Arm/Group Title	Family History Positive (FHP)		Family History Negative (FHN)
Arm/Group Description	People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism.		People who have no affected first- or second-degree relatives.
All Cause Mortality
	Family History Positive (FHP)		Family History Negative (FHN)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/36 (0%)
Serious Adverse Events
	Family History Positive (FHP)		Family History Negative (FHN)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Family History Positive (FHP)		Family History Negative (FHN)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/35 (68.6%)		26/36 (72.2%)
General disorders
Dizziness	14/35 (40%)	14	12/36 (33.3%)	12
Lightheaded	19/35 (54.3%)	19	17/36 (47.2%)	17
"Drunk" or "Tipsy"	5/35 (14.3%)	5	2/36 (5.6%)	2
Nausea	2/35 (5.7%)	2	2/36 (5.6%)	2
Vomit	0/35 (0%)	0	1/36 (2.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.