Clinical trial NCT05570812: Neuroactive Steroid to Treat Depressed Mood: A Trial for People With HIV
Official title: In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living With HIV
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Major Depressive Disorder
Anxiety Depression
HIV
Keywords: HIV
Depression
Neuroactive Steroid
Pregnenolone
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
name: Institute for Medical Research, Inc.
First posted: 2022-10-07
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized to receive oral pregnenolone or placebo.
Primary purpose: TREATMENT

Brief summary: This study will determine the effects of pregnenolone on brain function, inflammation and depressive symptoms in people with HIV who have depression. Participants in this study will receive a pill of either pregnenolone or placebo, and can stay on their current antidepression medications. Brain imaging and behavioral assessments will be performed during the study.

Detailed description: Pregnenolone is a neuroactive steroid that exhibits actions highly relevant to treating depression in people with HIV. The investigators' recent human data suggest that neuroactive steroids are decreased in people with HIV and depression. In addition, multiple groups have reported reductions in neuroactive steroids in people without HIV who have depression. A total of 120 people living with HIV on antiretroviral therapy with depression will be randomized to either pregnenolone or placebo (2 groups/90 participants receiving pregnenolone and 30 participants receiving placebo). Drug dosage will begin at 50 mg daily and incrementally increase to 500 mg daily within the first 4 weeks, with a stable 500 mg/day regimen for the final 4 weeks. Behavioral testing and blood draw will be performed at baseline, 2 weeks, 4 weeks, and 8 weeks, while magnetic resonance spectroscopy (MRS), and task-based functional magnetic resonance imaging (MRI) will be conducted at 2 weeks and 8 weeks.

The investigators hypothesize that pregnenolone will be well-tolerated in people with HIV and depression, and that this intervention may improve brain activity and reduce inflammation.

Eligibility criteria: Inclusion Criteria:

* 18-85 years
* HIV-1 viral load \<200 copies/mL on antiretroviral therapy (ART) at screening visit
* Center for Epidemiological Studies - Depression (CES-D) score ≥ 20

Exclusion Criteria:

* Contraindication to magnetic resonance imaging (MRI) or poor-quality baseline MRI preventing image analyses as determined by radiologist assessment
* Recent severe infections including opportunistic infections, active bacterial, mycobacterial, fungal, or certain viral infections
* Vulnerable populations (e.g., pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
* Use of cobicistat or ritonavir
* High risk for suicide (active suicidal ideation (SI) with plan/intent as assessed by using the Columbia Suicide Severity Rating (C-SSRS) or \> 2 attempts in lifetime or any in the past 6 months) or expresses homicidal ideation necessitating clinical intervention or representing an imminent concern
* Any severe (life-threatening or unstable) medical condition as determined by clinician assessment
* Blood pressure, with the lowest reading taken after three repeat readings during screening visit, ≥ 160 mmHg systolic OR ≥ 95 mmHg diastolic or other life-threatening vital signs as determined by clinician assessment
* Clinically significant abnormalities in physical examination or ECG that would interfere with study participation
* Decompensated cirrhosis, active liver inflammation (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≥ 5 times the upper limit of normal) or unsuppressed viral hepatitis B or C infection
* Severe renal disease (estimated glomerular filtration rate ≤ 30 mL/min/1.73m2)
* Seizure disorder requiring antiepileptic treatment
* History of allergic reaction or side effects with prior pregnenolone use
* Currently using testosterone enanthate, testosterone cypionate, and specific preparations containing estrogen. Other forms of exogenous sex steroid hormones will be evaluated at the discretion of the PI and/or clinical delegates.
* Currently using systemic immunosuppressive agents, including corticosteroids, chemotherapy, or specific immunomodulating agents, such as monoclonal antibodies and TNF-inhibitors
* Excessive alcohol or other substances use that would interfere with classification of major depression disorder, study procedures and/or follow-up
* Current diagnosis of bipolar disorder
* Diagnosis of a psychotic disorder (current or lifetime)
* Diagnosis of schizophrenia (current or lifetime)
* \<70% adherence to study drug prior to randomization
* Inability to swallow pills/capsules
* Not able to complete neuropsychological testing in English
* Concurrent participation in another interventional trial, except for lifestyle and device studies (For vaccination studies, individuals in the observation period are not exclusionary. Other interventions will be evaluated at the discretion of the PI and/or clinical delegates.)

Primary outcomes:
measure: Gamma-aminobutyric acid (GABA) Concentration
timeFrame: Day 14, Day 56
Secondary outcomes:
measure: Center for Epidemiological Studies-Depression (CES-D; scores range from 0 (no symptoms) to 60 (maximum severity of depressive symptoms))
timeFrame: Day 0, Day 14, Day 56
measure: CD14+CD16+ Monocytes
timeFrame: Day 0, Day 14, Day 28, Day 56
measure: GABA Concentration in Responders
timeFrame: Day 0, Day 14, Day 56
measure: Adverse Events
timeFrame: Day 14, Day 56
measure: Dose Modifications
timeFrame: Day 14, Day 56
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Shibani S. Mukerji, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mukerji SS, Misra V, Lorenz DR, Chettimada S, Keller K, Letendre S, Ellis RJ, Morgello S, Parker RA, Gabuzda D. Low Neuroactive Steroids Identifies a Biological Subtype of Depression in Adults with Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy. J Infect Dis. 2021 May 20;223(9):1601-1611. doi: 10.1093/infdis/jiaa104.