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

Primary Purpose

Major Depressive Disorder, Anxiety Depression, HIV

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Placebo
Pregnenolone
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Major Depressive Disorder focused on measuring HIV, Depression, Neuroactive Steroid, Pregnenolone

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Massachusetts General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Placebo

Pregnenolone

Arm Description

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

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

Outcomes

Primary Outcome Measures

Gamma-aminobutyric acid (GABA) Concentration
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))
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
Comparison of the Percentage of CD14+CD16+ Monocytes Over Time Adjusted for Baseline Between Pregnenolone and Placebo Groups
GABA Concentration in Responders
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
Comparison of the Incidence and Severity of Adverse Events Between Pregnenolone and Placebo Groups
Dose Modifications
Comparison of Dose Modifications Required Between Pregnenolone and Placebo Groups

Full Information

First Posted
October 4, 2022
Last Updated
August 7, 2023
Sponsor
Massachusetts General Hospital
Collaborators
National Institute of Mental Health (NIMH), Institute for Medical Research, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT05570812
Brief Title
Neuroactive Steroid to Treat Depressed Mood: A Trial for People With HIV
Acronym
SOOTHE
Official Title
In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living With HIV
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 3, 2023 (Actual)
Primary Completion Date
September 2027 (Anticipated)
Study Completion Date
January 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
National Institute of Mental Health (NIMH), Institute for Medical Research, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder, Anxiety Depression, HIV
Keywords
HIV, Depression, Neuroactive Steroid, Pregnenolone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Participants will be randomized to receive oral pregnenolone or placebo.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
This is a randomized, double-blind, placebo-controlled trial. All roles will be masked except the research pharmacist and statistician.
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Experimental
Arm Description
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
Arm Title
Pregnenolone
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
(4-week ramp, 4-week steady dosing)
Intervention Type
Drug
Intervention Name(s)
Pregnenolone
Other Intervention Name(s)
Neuroactive steroid
Intervention Description
(4-week ramp, 4-week steady dosing)
Primary Outcome Measure Information:
Title
Gamma-aminobutyric acid (GABA) Concentration
Description
Comparison between Pregnenolone and Placebo Groups of Left Insular Cortex GABA Concentration, Adjusted for Baseline.
Time Frame
Day 14, Day 56
Secondary Outcome Measure Information:
Title
Center for Epidemiological Studies-Depression (CES-D; scores range from 0 (no symptoms) to 60 (maximum severity of depressive symptoms))
Description
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.
Time Frame
Day 0, Day 14, Day 56
Title
CD14+CD16+ Monocytes
Description
Comparison of the Percentage of CD14+CD16+ Monocytes Over Time Adjusted for Baseline Between Pregnenolone and Placebo Groups
Time Frame
Day 0, Day 14, Day 28, Day 56
Title
GABA Concentration in Responders
Description
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
Time Frame
Day 0, Day 14, Day 56
Title
Adverse Events
Description
Comparison of the Incidence and Severity of Adverse Events Between Pregnenolone and Placebo Groups
Time Frame
Day 14, Day 56
Title
Dose Modifications
Description
Comparison of Dose Modifications Required Between Pregnenolone and Placebo Groups
Time Frame
Day 14, Day 56

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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 repeat testing 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 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 exogenous sex steroids hormones such as preparations containing estrogen or testosterone Currently using 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) <75% adherence to study drug prior to baseline MRI 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.)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hemi Park, MPH
Phone
857-282-3788
Email
MGHSOOTHE@PARTNERS.ORG
First Name & Middle Initial & Last Name or Official Title & Degree
Shibani S. Mukerji, MD, PhD
Phone
617-643-0666
Email
SMUKERJI@PARTNERS.ORG
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shibani S. Mukerji, MD, PhD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shibani Mukerji, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32157292
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.
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Neuroactive Steroid to Treat Depressed Mood: A Trial for People With HIV

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