Clinical trial NCT05849038: Inflammation and Depression in People With HIV
Official title: The Role of Inflammation in Central Nervous System (CNS) Mechanisms of Anhedonia and Psychomotor Slowing in Depressed People With HIV
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: HIV
Depression
Anhedonia
Keywords: Human Immunodeficiency Virus (HIV)
Anhedonia
Psychomotor Slowing
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2023-05-08
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this 10-week, double-blind, placebo-controlled study is to determine whether inflammation impacts reward and motor neural circuitry to contribute to depressive symptoms like anhedonia and psychomotor slowing in people with Human Immunodeficiency Virus (HIV) and depression. Sixty male and female patients with HIV who have depression, anhedonia and high inflammation and are stable on effective treatment for their HIV will be randomized to receive either the anti-inflammatory drug baricitinib or a placebo for 10 weeks. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing, functional MRI (fMRI) scans, and optional spinal taps as part of the study.

Detailed description: Risk of depression is substantially higher in people with HIV (PWH) than the general population, and depression in PWH confers worse outcomes regarding treatment adherence, morbidity, and mortality. Increased inflammation is one biological pathway that is linked to greater risk for depression in PWH and limits options for effective antidepressant therapy. Chronically elevated inflammation is associated with impairments within reward and motor neural circuits that contribute to symptoms of anhedonia (an inability to experience pleasure) and psychomotor slowing, which are overrepresented in PWH. The purpose of this 10-week, double-blind, placebo-controlled study is to provide mechanistic information on whether inflammation impacts corticostriatal reward and motor circuitry to contribute to anhedonia and psychomotor slowing in PWH with depression using the anti-inflammatory drug baricitinib.

This study will utilize an FDA-approved medication, baricitinib, to establish whether the effects of inflammation on reward and motor circuits are a mechanism of anhedonia and motor slowing in PWH with depression, while advancing avenues for new therapies.

Sixty male and female patients with HIV who have depression and high inflammation and are stable on effective treatment for their HIV will be randomized to receive either baricitinib or a placebo for 10 weeks. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing, functional MRI (fMRI) scans, and optional spinal taps as part of the study.

Eligibility criteria: Inclusion Criteria:

* HIV infected on continuous antiretroviral therapy (ART) with plasma HIV RNA \<200 copies/ml for at least 12 months (on at least two previous clinic visits and confirmed at screening)
* Current cluster of differentiation 4 (CD4+) \> 350 cells/microliter for at least twelve months (on at least two previous clinic visits and confirmed at screening)
* A primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) major depression, current, or Bipolar, depressed type as diagnosed by the SCID-V
* Score of ≥10 on the 9-item Patient Health Questionnaire (PHQ-9)
* Off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, and sedative hypnotics) for at least 4 weeks (8 weeks for fluoxetine) or on a stable psychotropic regimen for at least 4 weeks prior to baseline visit
* Significant anhedonia as reflected by a score ≥ 2 on item #1 of the PHQ-9
* CRP≥2mg/L
* Women of reproductive age will have a negative serum pregnancy test at study entry and both mend and women must agree to adequate contraception while

Exclusion Criteria:

* \< 18 years of age or \> 65 years of age
* Pregnancy or breastfeeding
* Significant hematological abnormalities at screening (ANC \< 1500, Hgb\<10, platelet\< 100,000)
* History of progressive multifocal leukoencephalopathy
* Untreated latent tuberculosis infection (which will be screened for prior to entry)
* Having taken the following immunosuppressive medications within the past 6 months:

  1. Oral corticosteroids
  2. Biologic treatments such as etanercept, infliximab, certolizumab, adalimumab, golimumab, tocilizumab, abatacept, Ustekinumab, ixekizumab, secukinumab, or anakinra
  3. Cyclophosphamide (or any other cytotoxic agent), belimumab, or anifrolumab (or another anti-interferon (IFN) therapy)
  4. Rituximab, any other B cell depleting therapies, or intravenous immunoglobulin (IVIg)
  5. any Janus kinase (JAK) inhibitor
* History of deep venous thrombosis
* Cardiovascular disease:

  1. Coronary artery disease or history of myocardial infarction
  2. Congestive heart failure with left ventricular ejection fraction ≤40% per American Heart Association guidelines
  3. Stroke history
* Hematologic malignancies including lymphoma and leukemia
* Major surgery within 8 weeks prior to screening or will require major surgery during the study
* Current or recent (\<4 weeks prior to randomization) clinically serious viral (including coronavirus disease 2019 (COVID-19)), bacterial, fungal, or parasitic infection or any other active or recent infection
* Symptomatic herpes simplex at the time of randomization
* Symptomatic herpes zoster infection within 12 weeks prior to randomization
* History of disseminated/complicated herpes zoster (for example, ophthalmic zoster or CNS involvement)
* Positive test for hepatitis B virus (HBV) defined as:

  1. positive for hepatitis B surface antigen (HBsAg), or
  2. positive for hepatitis B core antibody (HBcAb) and positive for hepatitis B virus deoxyribonucleic acid (HBV DNA)
* Hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV ribonucleic acid \[RNA\]-positive)
* Cirrhosis of the liver from any cause
* Any of the following specific abnormalities on screening laboratory tests:

  1. alanine transaminase (ALT) or aspartate aminotransferase (AST) \>2 x upper limits of normal (ULN)
  2. alkaline phosphatase (ALP) ≥2 x ULN
  3. total bilirubin ≥1.5 x ULN (with the exception of patients on atazanavir, who must have total bilirubin \<2 x ULN)
* Chronic kidney disease with estimated glomerular filtration rate (eGFR) \<40 mL/min/1.73 m\^2
* History of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; substance abuse/dependence within 6 months of study entry, as determined by severe combined immunodeficiency (SCID)
* A positive urine drug screen for illicit drugs at any time during the study excluding marijuana
* An active suicidal plan as determined by a score \>3 on item #3 on the Hamilton Rating Scale for Depression (HAM-D)
* An active eating disorder or antisocial personality disorder
* History of dementia
* Chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing medications or minocycline within 2 weeks of baseline or at any time during the study
* Any contraindication for MRI scanning
* Failure of more than 2 antidepressant trials (at least 6 weeks at recommended dose) in the current episode or 5 antidepressant trials lifetime
* BMI \>42 (to exclude severe obesity) or at the investigator's discretion based on the patient's ability to fit in the MRI scanner

Primary outcomes:
measure: Change in corticostriatal functional connectivity (FC) in reward circuit
timeFrame: Baseline visit, week 2, and week 10 after study medication
Secondary outcomes:
measure: Change in Effort Expenditure for Reward Task (EEfRT) Score
timeFrame: Baseline visit, week 2, and week 10
measure: Change in Snaith-Hamilton Pleasure Scale-Self Report (SHAPS-SR) Score
timeFrame: Baseline visit, week 1, week 2, week 4, week 6, and week 10
measure: Change in Motivation and Pleasure Scale-Self-Report (MAP-SR) Score
timeFrame: Baseline visit, week 1, week 2, week 4, week 6, and week 10
measure: Change in Inventory of Depressive Symptoms Self Report (IDS-SR) Anhedonia Subscale Score
timeFrame: Baseline visit, week 1, week 2, week 4, week 6, and week 10
measure: Change in Multidimensional Fatigue Inventory (MFI) Score
timeFrame: Baseline visit, week 1, week 2, week 4, week 6, and week 10
measure: Change in Finger Tapping Task (FTT) Mean Number of Taps
timeFrame: Baseline visit, week 2, and week 10
measure: Change in Finger Tapping Task (FTT) Total Number of Taps
timeFrame: Baseline visit, week 2, and week 10
measure: Change in Trail Making Test Part A (TMT-A) Score
timeFrame: Baseline visit, week 2, and week 10
measure: Change in Trail Making Test Part B (TMT-B) Score
timeFrame: Baseline visit, week 2, and week 10
measure: Change in Digit Symbol Substitution Test (DSST) Score
timeFrame: Baseline visit, week 2, and week 10
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
Study officials:
affiliation: Emory University
name: Andrew H Miller, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Jennifer Felger, PhD
role: PRINCIPAL_INVESTIGATOR
References: