SOOTHE: Neuroactive Steroid to Treat Depressed Mood: A Trial for People With HIV

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05570812

Collaborator

National Institute of Mental Health (NIMH) (NIH), Institute for Medical Research, Inc. (Industry)

120

Enrollment

Arms

51.3

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This study will determine the effects of pregnenolone on brain function, inflammation and depressive symptoms in people living 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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder Anxiety Depression Hiv	Drug: Placebo Drug: Pregnenolone	Phase 2

Detailed Description

Pregnenolone is a neuroactive steroid that exhibits actions highly relevant to treating depression in people living with HIV. The investigators' recent human data suggest that neuroactive steroids are decreased in people living 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, 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 living with HIV and depression, and that this intervention may improve brain activity and reduce inflammation.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be randomized to receive oral pregnenolone or placebo.Participants will be randomized to receive oral pregnenolone or placebo.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

This is a randomized, double-blind, placebo-controlled trial. All roles will be masked except the research pharmacist and statistician.

Primary Purpose:

Treatment

Official Title:

In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living With HIV

Anticipated Study Start Date :

Feb 20, 2023

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Jun 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks	Drug: Placebo (4-week ramp, 4-week steady dosing)
Experimental: Pregnenolone Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks	Drug: Pregnenolone (4-week ramp, 4-week steady dosing) Other Names: Neuroactive steroid

Arm

Intervention/Treatment

Experimental: Placebo

Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks

Drug: Placebo

(4-week ramp, 4-week steady dosing)

Experimental: Pregnenolone

Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks

Drug: Pregnenolone

(4-week ramp, 4-week steady dosing)

Other Names:

Neuroactive steroid

Outcome Measures

Primary Outcome Measures

Gamma-aminobutyric acid (GABA) Concentration [Day 14, Day 56]
Comparison between Pregnenolone and Placebo Groups of Left Insular Cortex GABA Concentration, Adjusted for Baseline.

Secondary Outcome Measures

Center for Epidemiological Studies-Depression (CES-D; scores range from 0 (no symptoms) to 60 (maximum severity of depressive symptoms)) [Day 0, Day 14, Day 56]
Comparison of Percentage of Pregnenolone and Placebo Groups Showing Clinical Improvement of Depression at Study End. The revised CES-D is administered, and the total score is calculated by adding the responses to the 20 questions.
CD14+CD16+ Monocytes [Day 0, Day 14, Day 28, Day 56]
Comparison of the Percentage of CD14+CD16+ Monocytes Over Time Adjusted for Baseline Between Pregnenolone and Placebo Groups
GABA Concentration in Responders [Day 0, Day 14, Day 56]
Comparison of Baseline Left Insular Cortex GABA and Pregnenolone Between Participants in Pregnenolone Group with Clinical Improvement Compared to Clinical Non-Improvers in Pregnenolone Group
Adverse Events [Day 14, Day 56]
Comparison of the Incidence and Severity of Adverse Events Between Pregnenolone and Placebo Groups
Dose Modifications [Day 14, Day 56]
Comparison of Dose Modifications Required Between Pregnenolone and Placebo Groups

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

18-70 years
HIV-1 viral load <200 copies/mL on antiretroviral therapy
Center for Epidemiological Studies - Depression (CES-D) score ≥ 20

Exclusion Criteria:

Contraindication to magnetic resonance imaging
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 repeat testing during screening visit, ≥ 140 mmHg systolic OR ≥ 90 mmHg diastolic or other life-threatening vital signs as determined by clinician assessment
Clinically significant abnormalities in physical examination or ECG
Cirrhosis or active liver inflammation (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≥ 5 times the upper limit of normal) or untreated viral hepatitis diagnosis of alcohol use disorder
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 hormone replacement therapy
Currently using immunomodulators (e.g. corticosteroids, tumor necrosis factor (TNF) -inhibitors)
Excessive alcohol or other substances use that would interfere with study procedures and/or follow-up
Diagnosis of bipolar disorder (current or lifetime)
Diagnosis of a psychotic disorder (current or lifetime)
Diagnosis of schizophrenia (current or lifetime)
Inability to swallow pills/capsules
Not able to complete neuropsychological testing in English