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Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the mGluR5 Inhibitor Mavoglurant

Primary Purpose

Familial Alcoholism Vulnerability

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Mavoglurant (AFQ056)
Placebo
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Familial Alcoholism Vulnerability

Eligibility Criteria

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

Inclusion Criteria:

  • Ages 18-45 years
  • Estimated full-scale IQ>70
  • Individual can cooperate with all study procedures
  • No history of neurological disorder (e.g., epilepsy)
  • No major medical condition (e.g., cancer)
  • No history of significant head trauma
  • Stable medication treatment 6 weeks prior to study enrollment
  • Negative urine drug and breathe alcohol test at time of MRI scan
  • Negative urine pregnancy test at time of MRI scan
  • No MR contra-indications (e.g., in-body metal implant, severe claustrophobia)
  • No contra-indications to study drug

Exclusion Criteria:

  • A diagnosis of any psychotic disorder, or current mood or anxiety disorders under DSM-V, using the SCID-V-RV psychiatric interview
  • A current diagnosis of: a) Alcohol use disorder, if severe (AUD, mild or moderate OK if no craving, tolerance, and withdrawal 3 months prior to interview) b) Substance use disorder
  • Report of psychotic disorder in a 1º relative
  • Auditory or visual impairment that interferes with test-taking
  • Prenatal exposure to alcohol plus currently meeting criteria for features of fetal alcohol syndrome
  • Not speaking English fluently or being a non-native English speaker, or being educated in a primary language other than English > grade 1
  • Intellectual Disability (Full Scale IQ<70)
  • Traumatic brain injury with loss of consciousness > 30 minutes or concussion in last 30 days
  • Presence or history of neurosurgery or any 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 board certified radiologist)
  • A current major medical condition (e.g. cancer, heart failure)
  • Current pregnancy (all females will be tested with urine screens on the day of MRI)
  • Women not on an effective form of birth control/contraception or abstinent during time of study visits to prevent exposure of the investigational drug to suspected fetus
  • Current substance use with the exception of marijuana (THC), provided last use of THC was 24+ hours before visit (All participants will receive a urine screen for the presence of marijuana, cocaine, opiates and a breath screen to detect the presence of alcohol)
  • Inability to comprehend the consent form appropriately
  • Inability to cooperate with study procedures
  • Other specific fMRI exclusions include metal devices, clips or fragments in body (orbital xray performed if needed)

Sites / Locations

  • Hartford HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

FHP; Mavoglurant-Placebo

FHP; Placebo-Mavoglurant

FHN; Mavoglurant-Placebo

FHN; Placebo-Mavoglurant

Arm Description

Family History Positive (FHP) for alcoholism will be given a single dose of AFQ056 (200 mg) then placebo in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

Family History Positive (FHP) or alcoholism will be given a single dose of placebo then AFQ056 (200 mg) in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

Family History Negative (FHN) for alcoholism will be given a single dose of AFQ056 (200 mg) then placebo in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

Family History Negative (FHN) for alcoholism will be given a single dose of placebo then AFQ056 (200 mg) in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.

Outcomes

Primary Outcome Measures

Change in Nucleus accumbens (Nacc)/Ventral striatum (VS) BOLD activation during A1 phase in FHP on study medication vs. placebo
Changes in NAcc/VS BOLD (Blood-oxygen-level-dependent) activation during the A1 loss anticipation prospect phase of the MRI Monetary Incentive Delay task in FHP while on mavoglurant compared to placebo
BOLD activation to alcohol vs. non-alcohol stimuli during ACR task alcohol versus non-alcohol stimuli
Changes in BOLD response in FHP to alcohol versus non-alcohol stimuli in several brain clusters containing MFC, caudate, parahippocampal gyrus, temporal cortex and cerebellum, when administered mavoglurant compared to placebo

Secondary Outcome Measures

Dynamic Causal Modeling (DCM)-determined relationships between nucleus accumbens (NAcc) and -medial PFC BOLD signal during MSDM task
Dynamic Causal Modeling (DCM)-determined relationships between nucleus accumbens (NAcc) and -medial PFC BOLD signal during MSDM fMRI task in FHP while on mavoglurant compared to placebo
Regional differences in BOLD signal
Impairment of top down inhibitory control and related cortical activation of the executive control network in FHP while on mavoglurant compared to placebo measured by regional differences in BOLD signaling

Full Information

First Posted
January 5, 2022
Last Updated
March 30, 2023
Sponsor
Yale University
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1. Study Identification

Unique Protocol Identification Number
NCT05203965
Brief Title
Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the mGluR5 Inhibitor Mavoglurant
Official Title
Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the mGluR5 Inhibitor Mavoglurant
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 17, 2022 (Actual)
Primary Completion Date
July 31, 2024 (Anticipated)
Study Completion Date
July 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Yale University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the role of Mavoglurant in clarifying the neurobiology of alcoholism risk. This is a one-site, randomized, within subjects, counterbalanced double-blind study of a single dose (200mg) of Mavoglurant and placebo.
Detailed Description
This project explores the effects of 1 dose of Mavoglurant, an experimental non-competitive antagonist to metabotropic glutamate receptor-5 (mGlur5) developed by Novartis, in a double-blind, randomized, counterbalanced manner on alcoholism risk-relevant tasks. Drug/placebo will be administered on 2 separate visits separated by 1 week. More specifically, this project examines 4 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 N-methyl-D-Aspartate and Dopamine (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, as well as conventional within-task analyses, functional network connectivity and allied approaches will be used to examine brain networks across the tasks.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Prevention
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
FHP; Mavoglurant-Placebo
Arm Type
Experimental
Arm Description
Family History Positive (FHP) for alcoholism will be given a single dose of AFQ056 (200 mg) then placebo in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.
Arm Title
FHP; Placebo-Mavoglurant
Arm Type
Experimental
Arm Description
Family History Positive (FHP) or alcoholism will be given a single dose of placebo then AFQ056 (200 mg) in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.
Arm Title
FHN; Mavoglurant-Placebo
Arm Type
Experimental
Arm Description
Family History Negative (FHN) for alcoholism will be given a single dose of AFQ056 (200 mg) then placebo in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.
Arm Title
FHN; Placebo-Mavoglurant
Arm Type
Experimental
Arm Description
Family History Negative (FHN) for alcoholism will be given a single dose of placebo then AFQ056 (200 mg) in two separate experimental study visits separated by 1 week. Drug and Placebo administered 2 hours prior to the MRI and other measures.
Intervention Type
Drug
Intervention Name(s)
Mavoglurant (AFQ056)
Intervention Description
Two 100mg tablets of Mavoglurant will be administered on the morning of one of the two experimental days by a RN or the physician investigator.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Two matching tablets of placebo will be administered on the morning of one of the two experimental days by an RN or the physician investigator.
Primary Outcome Measure Information:
Title
Change in Nucleus accumbens (Nacc)/Ventral striatum (VS) BOLD activation during A1 phase in FHP on study medication vs. placebo
Description
Changes in NAcc/VS BOLD (Blood-oxygen-level-dependent) activation during the A1 loss anticipation prospect phase of the MRI Monetary Incentive Delay task in FHP while on mavoglurant compared to placebo
Time Frame
Mavoglurant and Placebo administration are 1 week apart
Title
BOLD activation to alcohol vs. non-alcohol stimuli during ACR task alcohol versus non-alcohol stimuli
Description
Changes in BOLD response in FHP to alcohol versus non-alcohol stimuli in several brain clusters containing MFC, caudate, parahippocampal gyrus, temporal cortex and cerebellum, when administered mavoglurant compared to placebo
Time Frame
Mavoglurant and Placebo administration are 1 week apart
Secondary Outcome Measure Information:
Title
Dynamic Causal Modeling (DCM)-determined relationships between nucleus accumbens (NAcc) and -medial PFC BOLD signal during MSDM task
Description
Dynamic Causal Modeling (DCM)-determined relationships between nucleus accumbens (NAcc) and -medial PFC BOLD signal during MSDM fMRI task in FHP while on mavoglurant compared to placebo
Time Frame
Mavoglurant and Placebo administration are 1 week apart
Title
Regional differences in BOLD signal
Description
Impairment of top down inhibitory control and related cortical activation of the executive control network in FHP while on mavoglurant compared to placebo measured by regional differences in BOLD signaling
Time Frame
Mavoglurant and Placebo administration are 1 week apart

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Ages 18-45 years Estimated full-scale IQ>70 Individual can cooperate with all study procedures No history of neurological disorder (e.g., epilepsy) No major medical condition (e.g., cancer) No history of significant head trauma Stable medication treatment 6 weeks prior to study enrollment Negative urine drug and breathe alcohol test at time of MRI scan Negative urine pregnancy test at time of MRI scan No MR contra-indications (e.g., in-body metal implant, severe claustrophobia) No contra-indications to study drug Exclusion Criteria: A diagnosis of any psychotic disorder, or current mood or anxiety disorders under DSM-V, using the SCID-V-RV psychiatric interview A current diagnosis of: a) Alcohol use disorder, if severe (AUD, mild or moderate OK if no craving, tolerance, and withdrawal 3 months prior to interview) b) Substance use disorder Report of psychotic disorder in a 1º relative Auditory or visual impairment that interferes with test-taking Prenatal exposure to alcohol plus currently meeting criteria for features of fetal alcohol syndrome Not speaking English fluently or being a non-native English speaker, or being educated in a primary language other than English > grade 1 Intellectual Disability (Full Scale IQ<70) Traumatic brain injury with loss of consciousness > 30 minutes or concussion in last 30 days Presence or history of neurosurgery or any 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 board certified radiologist) A current major medical condition (e.g. cancer, heart failure) Current pregnancy (all females will be tested with urine screens on the day of MRI) Women not on an effective form of birth control/contraception or abstinent during time of study visits to prevent exposure of the investigational drug to suspected fetus Current substance use with the exception of marijuana (THC), provided last use of THC was 24+ hours before visit (All participants will receive a urine screen for the presence of marijuana, cocaine, opiates and a breath screen to detect the presence of alcohol) Inability to comprehend the consent form appropriately Inability to cooperate with study procedures Other specific fMRI exclusions include metal devices, clips or fragments in body (orbital xray performed if needed)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Godfrey D Pearlson, MD
Phone
203-737-3416
Email
godfrey.pearlson@hhchealth.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Godfrey D Pearlson, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hartford Hospital
City
Hartford
State/Province
Connecticut
ZIP/Postal Code
06106
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Godfrey D Pearlson, MD
Phone
203-737-3416
Email
godfrey.pearlson@hhchealth.org
First Name & Middle Initial & Last Name & Degree
Godfrey D Pearlson, MD

12. IPD Sharing Statement

Learn more about this trial

Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the mGluR5 Inhibitor Mavoglurant

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