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HCV and Co-morbid Alcohol Use Disorders: A Translational Investigation of Antiviral Therapy Outcomes on CNS Function

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ClinicalTrials.gov Identifier: NCT03902366
Recruitment Status : Recruiting
First Posted : April 4, 2019
Last Update Posted : May 21, 2019
Sponsor:
Collaborators:
Oregon Health and Science University
Portland VA Medical Center
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:

The primary objective of this research project is to compare neuropsychiatric functioning, cortical activity, white matter integrity, and immune response among Veterans with and without alcohol use disorder (AUD), before and after direct-acting antiviral (DAA) therapy [a new treatment for chronic infection with the hepatitis C virus (HCV)]. Demographically-matched comparison groups of Veterans without HCV (HCV-, with and without AUD) will similarly be evaluated to determine the relative contribution of HCV and an HCV "cure" to outcomes putatively affected by alcohol abuse.

Two specific aims are proposed.

Aim 1: Determine the impact of DAA therapy and a sustained viral response on central nervous system (CNS) function.

Aim 2: Evaluate the effects of AUD and unhealthy alcohol drinking on DAA therapy outcomes and CNS function.

The information learned will address a critical gap in knowledge concerning the effects of alcohol use on DAA therapy outcomes and will help inform treatment guidelines that could be translated to clinical practice, such as targeted interventions to treat AUD in conjunction with HCV infection and follow-up strategies for patients who successfully complete DAA therapy but then need care for other potential CNS-related outcomes.


Condition or disease Intervention/treatment
Hepatitis C Alcohol Use Disorder Diagnostic Test: Neuropsychological assessment Behavioral: Neuroimaging

Detailed Description:

Aim 1 will evaluate the impact of DAA therapy on CNS function in Veterans with HCV and will test the hypotheses that following DAA therapy and obtaining a sustained viral response [SVR; i.e., when the virus continues to be undetectable in blood 12 weeks (or more) after completing therapy], participants will show: i) improved neuropsychiatric outcomes (e.g., cognitive function, fatigue, mood), as compared to baseline (pre-DAA therapy), ii) restored functional connectivity and disintegrity within white matter tracks that had been observed at baseline, and iii) reduced immune activation profiles (e.g., decreased expression of inflammatory biomarkers and restored T cell balance), as compared to baseline. Aim 2 will determine the impact of an active AUD on the neuropsychiatric, neuroimaging, and immunological outcomes observed in aim 1. Participants will be evaluated at two time points [i.e., baseline and 12 weeks post-therapy (week 24)]. Evaluations will incorporate brain imaging methods [i.e., resting state magnetic resonance imaging (MRI), functional MRI, and diffusion tensor imaging] along with clinical and laboratory methods to assess the interactive effects of alcohol use and HCV on brain function. Clinical and laboratory data will include: i) demographic and medical information, ii) neuropsychological measures of attention, memory, and executive function, iii) neuropsychiatric symptom questionnaires (e.g., depression and anxiety), iv) urine and oral fluid collection for medical laboratory tests, and v) blood sample collection for planned experiments (e.g., flow cytometry, qPCR, and multiplex immunoassays) and for contribution to the VA Liver Disease Repository.

Evidence-based guidelines for the new DAA therapies are needed (e.g., How much alcohol is too much?). The VA is at the forefront of treating HCV and is now offering DAA therapy to all Veterans with HCV treated within VA health care systems. The proposed studies will address a critical gap in our knowledge concerning the effects of co-morbid HCV and AUD on antiviral therapy outcomes, particularly CNS function and neuropsychiatric symptoms that contribute to addiction and relapse.


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Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: HCV and Co-morbid Alcohol Use Disorders: A Translational Investigation of Antiviral Therapy Outcomes on CNS Function
Actual Study Start Date : May 16, 2019
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : October 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Alcohol

Group/Cohort Intervention/treatment
AUD+/HCV+
  • With current Alcohol Use Disorder and with HCV
  • About to initiate DAA therapy for HCV
Diagnostic Test: Neuropsychological assessment
Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).

Behavioral: Neuroimaging
Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.

AUD-/HCV+
  • Without current Alcohol Use Disorder and with HCV
  • About to initiate DAA therapy for HCV
Diagnostic Test: Neuropsychological assessment
Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).

Behavioral: Neuroimaging
Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.

AUD+/HCV-
-With Alcohol Use Disorder and without HCV
Diagnostic Test: Neuropsychological assessment
Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).

Behavioral: Neuroimaging
Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.

AUD-/HCV-
-Without Alcohol Use Disorder and without HCV
Diagnostic Test: Neuropsychological assessment
Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).

Behavioral: Neuroimaging
Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.




Primary Outcome Measures :
  1. Changes in Neuropsychological Assessment Battery (NAB) Attention Module Scores [ Time Frame: Baseline and 6 months ]
    The neuropsychological test battery measures an individual's attentional capacity, working memory, psychomotor speed, selective attention, divided attention, and information processing speed. Raw scores will be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test.

  2. Changes in Neuropsychological Assessment Battery (NAB) Memory Module Scores [ Time Frame: Baseline and 6 months ]
    The neuropsychological test assesses an individual's verbal explicit learning, visual explicit learning, verbal delayed free recall, visual delayed recognition memory, and verbal explicit learning and recognition of information likely to be encountered in daily living. Raw scores will be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test.

  3. Changes in Neuropsychological Assessment Battery (NAB) Executive Functions Module Scores [ Time Frame: Baseline and 6 months ]
    The neuropsychological test assesses executive function, such as problem-solving, planning, and mental flexibility. Raw scores will be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test.

  4. Changes in alcohol use measured using the Timeline Follow Back (TLFB) [ Time Frame: Baseline and 6 months ]
    The TLFB will be used to measure change across several dimensions of alcohol drinking behavior: (a) variability (i.e., scatter); (b) pattern (i.e., shape); and (c) extent of drinking (i.e., elevation/reduction; how much).

  5. Change in behavior as assessed by the Balloon Analogue Risk Task (BART) [ Time Frame: Baseline and 6 months ]
    The BART is a computerized measure of risk-taking behavior that concurrently measures several domains (i.e., risky decision-making, reward/negative outcome processing) during fMRI scanning.

  6. Change in behavior as assessed by the Monetary Incentive Delay (MID) task [ Time Frame: Baseline and 6 months ]
    The MID is a validated task to examine anticipatory brain responses to reward during fMRI scanning.

  7. Change in Fatigue Severity Scale (FSS) score [ Time Frame: Baseline and 6 months ]
    The Fatigue Severity Scale (FSS) is a 9-item self-report questionnaire designed to measure level of fatigue. The FSS is graded on a 7-point Likert-like scale ranging from 1 ("strongly disagree") to 7 ("strongly agree"). The minimum score is 9 and the maximum score possible is 63. A higher score represents a greater fatigue severity. The average score for all 9 items constitute the FSS score.

  8. Change in Beck Depression Inventory Second Edition (BDI-II) score [ Time Frame: Baseline and 6 months ]
    The Beck Depression Inventory Second Edition (BDI-II) is a 21-question multiple-choice self-report inventory that measures depression. There is a four-point scale for each item ranging from 0-3. The total score can range from 0 to 63 points. Higher scores reflect a great level of depression severity.

  9. Change in fractional anisotropy (FA) in white matter tracts [ Time Frame: Baseline and 6 months ]
    MRI-based diffusion tensor imaging (DTI) tractography is used to measure fractional anisotropy (an indicator of CNS microstructural integrity).

  10. Change in mean diffusivity in white matter tracks [ Time Frame: Baseline and 6 months ]
    MRI-based DTI tractography is used to measured mean diffusivity (an indicator of CNS microstructural integrity).

  11. Changes in inflammatory profile marker concentration [ Time Frame: Baseline and 6 months ]
    Immune factors in the inflammatory profile include: C-reactive protein (CRP), C-X-C motif chemokine (CXCL10), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-18 (IL-18), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-3 (MMP-3), S100 calcium binding protein B (S100B), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor alpha (TNF-alpha).

  12. Changes in T cell subpopulation frequency [ Time Frame: Baseline and 6 months ]
    T-cells will be evaluated for changes in the frequencies of double negative (DN; CD4-CD8-) and double positive (DP; CD4+CD8+) CD3+ cells.


Biospecimen Retention:   Samples With DNA
Blood specimens are collected from human subjects by study personnel or the VA phlebotomy lab specifically for research purposes. Research staff centrifuges the blood samples so that components [e.g., plasma, peripheral blood mononuclear cells (PBMCs)] can be collected, frozen, cryopreserved, and contributed to the VA Liver Disease Repository (Director: Dr. Lissi Hansen).


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Adult Veterans (> 21 years old) who are about to initiate DAA therapy for HCV are recruited into two demographically matched (i.e., similar in terms of age, gender, race, and years of education) groups (n = 30/group): 1) adults with current alcohol use disorder (AUD+/HCV+) and 2) adults without current AUDs (AUD-/HCV+). Two additional groups of demographically-matched adults: 1) without AUD or HCV (AUD-/HCV-) (n = 30), and 2) with AUD and no HCV (AUD+/HCV-) will be recruited as a comparison groups to determine the relative contribution of a history of HCV infection to alcohol-induced brain pathology.
Criteria

Inclusion Criteria:

  • Adult Veteran (>21 years)
  • Able to provide informed consent.

Exclusion Criteria:

  • Current substance use disorder other than alcohol (except nicotine or caffeine)
  • Medical conditions likely to impact immunological function or central nervous system function (such as HIV, cancer, lupus, stroke, neurodegenerative disease, hepatic encephalopathy, multiple sclerosis, or a traumatic brain injury)
  • Current opioid use of >20 MED per day
  • More than 30 days of benzo or opioid use in the last 6 months
  • Past or present schizophrenia, schizoaffective disorder, or current psychosis or mania
  • Visual or auditory impairments that would prevent valid neuropsychiatric testing
  • Contraindications to MRI (such as surgical aneurysm clips, pacemaker, prosthetic heart valve, neuro-stimulator, implanted pumps, cochlear implants, metal rods, plates or screws, previous surgery, hearing aids, history of welding, metal shrapnel)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03902366


Contacts
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Contact: Kate M Shirley, MA BA (503) 220-8262 ext 52470 kate.shirley@va.gov
Contact: Jennifer M Loftis, MA PhD Jennifer.Loftis2@va.gov

Locations
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United States, Oregon
VA Portland Health Care System, Portland, OR Recruiting
Portland, Oregon, United States, 97239
Contact: Kate M Shirley, MA BA    503-220-8262 ext 52470    kate.shirley@va.gov   
Principal Investigator: Jennifer M Loftis, MA PhD         
Sponsors and Collaborators
VA Office of Research and Development
Oregon Health and Science University
Portland VA Medical Center
Investigators
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Principal Investigator: Jennifer M Loftis, MA PhD VA Portland Health Care System, Portland, OR

Publications:
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT03902366     History of Changes
Other Study ID Numbers: NURA-007-17F
03967 ( Other Grant/Funding Number: Portland VA Medical Center )
First Posted: April 4, 2019    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:
Hepatitis C
Direct-acting antiviral therapies
DAA
Chronic HCV infection
Alcohol Use Disorder

Additional relevant MeSH terms:
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Disease
Hepatitis
Hepatitis C
Alcohol Drinking
Alcoholism
Pathologic Processes
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Drinking Behavior
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Ethanol
Antiviral Agents
Anti-Infective Agents, Local
Anti-Infective Agents
Central Nervous System Depressants
Physiological Effects of Drugs