Sex Differences in Trauma, Inflammation and Brain Function and the Implications for Treatment Efficacy in Alcohol Use Disorder

NCT06426303 | Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: 25536
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to identify sex-specific biomarkers that confer greater susceptibility for Alcohol Use Disorder (AUD) and differentiate how treatment response varies by sex in people with Alcohol Use Disorder. The main questions it aims to answer are:

• How does trauma affect emotion regulation, inflammation, and limbic function, and what are the sex-dependent effects of NTX (Naltrexone) on these aspects?
• What is the mechanism of Naltrexone (NTX), and how does it potentially moderate reductions in alcohol use through changes in or interactions between emotion regulation, inflammation, or limbic system function? Participants will
• Be consented and will undergo comprehensive screening for eligibility criteria
• Complete behavioral assessments and neuropsychological assessments, as well as neurocognitive assessments and neuroimaging measures
• Provide urine samples for a urine drug screen (UDS) and urine pregnancy test (for women), and have blood and a cheek swab collected and stored in the repository
• Take a study drug once daily for 12 weeks and track drug usage and effects in a study journal
• Undergo weekly assessment calls and bi-weekly medical follow-up safety exams Researchers will compare naltrexone to placebo in AUD to see if naltrexone is effective in reducing alcohol cravings and promoting abstinence. Researchers will also compare baseline measures between AUD and Healthy Controls.

Conditions

Alcohol Use Disorder

Keywords

Naltrexone

Outcome Measures

Primary Outcomes (6)

• Change from baseline in alcohol use (number of drinking days, amount used per day)

  Drinking days and average number of weekly standard drinks will be measured at baseline and at follow-up

  Baseline and Week 12

• Changes from baseline in peripheral immune biomarkers associated with inflammation

  Plasma samples will be analyzed using a customized, high-sensitivity magnetic bead multiplex assay Luminex system. Samples will be prepared and analyzed to measure peripheral immune markers: interleukin (IL)-1-beta, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, brain-derived neurotrophic factor (BDNF), monocyte chemotactic protein (MCP)-1 and neural cell adhesion molecule (NCAM). Intra-and inter-assay coefficients of variation, as indices of within-and between-assay precision, respectively, will be calculated to examine the reliability of cytokine measurements.

  Baseline and Week 12

• Changes in limbic functional connectivity

  Resting-state functional magnetic resonance imaging (rs-fMRI) will be used to assess changes in limbic system connectivity. Correlation coefficients of low-frequency oscillations in the fMRI blood oxygenation level dependent (BOLD) signal between regions and between large-scale resting-state networks in the brain will be z-score transformed. A score of 0 indicates no change while higher or lower scores indicate increased or decreased connectivity, respectively.

  Baseline and Week 12

• Changes from baseline in BOLD signal brain activation during an emotion regulation fMRI task

  The task will assess emotional reactivity and regulation to negative and stressful images. Each event (cue, neutral-look, negative-look, negative-reappraise and rating scale of negative affect) will be modeled using a canonical hemodynamic response function with a time derivative. The contrasts of interest will be Negative-look vs Neutral-look and Negative-look vs Negative-reappraise. Amygdala BOLD signal estimates will be extracted to calculate percent-change.

  Baseline and Week 12

• Changes from baseline in emotion regulation assessed with the Difficulty in Emotion Regulation Scale (DERS)

  DERS is a 36-item self-report questionnaire scored on a 5-point scale from 1 (almost never) to 5 (almost always), with total score ranging from 36 to 180. It measures emotion regulation difficulties across six dimensions: 1. Non-acceptance of emotional responses, 2. Difficulties engaging in goal-directed behavior, 3. Impulse control difficulties, 4. Lack of emotional awareness, 5. Limited access to effective emotion regulation strategies, 6. Lack of emotional clarity. Higher scores suggest greater difficulties in emotion regulation.

  Baseline and Week 12

• Changes from baseline in emotion regulation assessed with the Cognitive Emotion Regulation Questionnaire (CERQ)

  CERQ is a 36-item self-report questionnaire that identifies cognitive emotion regulation or cognitive coping strategies used after having experienced negative events or situations. Scores can identify individual strategies to compare with normed scores from various populations. The nine cognitive emotion regulation strategies are measured on a 5-point Likert scale ranging from 1 to 5, with scores being obtained by calculating the mean scores belonging to a particular subscale. Higher subscale scores indicate greater use of a specific cognitive strategy.

  Baseline and Week 12

Secondary Outcomes (3)

• Change from baseline in craving (include craving measures/questionnaires)

  Baseline and Week 12

• Differences in baseline trauma exposure (composite score)

  Baseline and Week 12

• Change from baseline in neuropsychological testing scores

  Baseline and Week 12

Study Arms (2)

Alcohol Use Disorder (AUD)

EXPERIMENTAL

Drug: Naltrexone Half of the study participants with AUD will take an oral tablet of 50 mg naltrexone once daily for one week followed by 11 weeks of 100 mg naltrexone orally, once daily. Drug: Placebo oral tablet The other half of study participants will receive an identical looking placebo in tablet form and take the medication using an identical schedule as the real drug. Drug type will be randomized.

Drug: Naltrexone

Healthy Controls

NO INTERVENTION

Baseline measures will be taken but controls will not continue to the drug trial.

Interventions

Naltrexone DRUG

12-week randomized double blinded placebo-controlled drug trial titrating drug/placebo dose after 1 week.

Also known as: Revia

Alcohol Use Disorder (AUD)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• years old
• Veteran enrolled in VHA healthcare
• Alcohol Group:
• must meet diagnosis for recent alcohol-use disorder (DSM-V)
• willing to return for follow-up visits and can participate for 12-weeks
• Control Group:
• must not meet DSM-V criteria for a use disorder other than nicotine

You may not qualify if:

• Clinically significant neurological, endocrine, hepatic, or systemic disease that would compromise safe participation or confound outcomes
• Left-handedness
• Axis-1 psychiatric diagnoses other than anxiety, depression or post-traumatic stress disorder
• Recreational or prescriptive use of psychotropic medications
• Recreational or prescriptive use of opioid medications or have a past or current history of abuse or dependence on opioids
• MRI contraindications (e.g. metal in body)
• Positive urine drug screen, except for nicotine and marijuana, on test days
• Women who are pregnant or breastfeeding
• Participants on hormonal therapy or treatments other than pregnancy contraceptives
• Autoimmune or neurodegenerative diseases that present with neuroinflammation (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, Parkinson's)
• Current participation in an investigational drug study
• Alcohol group: \< 5 days and \> 3 weeks of abstinence from alcohol
• Alcohol group: Liver disease requiring medication or medical treatment, and/or aspartate or alanine aminotransferase levels greater than 3 times the upper limit of normal, gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medical treatment.
• Non-english speaker

Sponsors & Collaborators

• Milky Kohno: lead
• Portland VA Medical Center: collaborator

Study Sites (1)

VA Portland Health Care System

Portland, Oregon, 97239, United States

RECRUITING

MeSH Terms

Conditions

Alcoholism

Interventions

Naltrexone

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Naloxone; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Central Study Contacts

Jazryn Nagum

CONTACT

503-721-7964; vhaporhoffmanlab@va.gov

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 19, 2024
• First Posted: May 23, 2024
• Study Start: May 2, 2024
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: July 18, 2024

Record last verified: 2024-07

Locations

US (1)