Development of Pregnenolone as a Treatment for Depression

NCT03645096 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: STU 052018-0301R61AT009625-01A1
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

Pregnenolone, an over-the-counter supplement, is a naturally occurring neurosteroid made in the adrenal glands and brain. Preclinical research suggests pregnenolone has antidepressant, cognitive enhancing, and neuroprotective properties, particularly in women. The following hypothesis will be tested in this trial: pregnenolone is associated with improvement in depressive symptom severity in women that is associated with changes in the resting state functional connectivity (rsFC) and GABA.

Conditions

Major Depressive Disorder

Keywords

Depression; Pregnenolone; Women

Outcome Measures

Primary Outcomes (3)

• Amygdala-PCC Functional Connectivity

  Determine if an increase in Amygdala-PCC functional connectivity is observed with pregnenolone as compared to placebo. Amygdala-PCC functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold).

  7 days

• dlPFC-Insula Functional Connectivity

  Determine if an increase in dlPFC-Insula functional connectivity is observed with pregnenolone as compared to placebo. dlPFC-Insula functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold).

  7 days

• GABA Concentration.

  Determine if an increase in occipital GABA concentration is observed with pregnenolone, as compared to placebo. Occipital GABA concentration using spectroscopy with tCr reference. Higher concentration values are representative of a greater anti-depressant effect.

  7 days

Secondary Outcomes (4)

• Pregnenolone Level

  7 days

• Allopregnanolone Level

  7 days

• Systematic Assessment for Treatment Emergent Events (SAFTEE)

  7 days

• Pregnenolone Dose

  7 days

Study Arms (6)

Pregnenolone 500 > Pregnenolone 800 > Placebo

EXPERIMENTAL

3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.

Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

Pregnenolone 500 > Placebo > Pregnenolone 800

EXPERIMENTAL

3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.

Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

Pregnenolone 800 > Pregnenolone 500 > Placebo

EXPERIMENTAL

3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.

Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

Pregnenolone 800 > Placebo > Pregnenolone 500

EXPERIMENTAL

3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.

Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

Placebo > Pregnenolone 500 > Pregnenolone 800

EXPERIMENTAL

3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.

Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

Placebo > Pregnenolone 800 > Pregnenolone 500

EXPERIMENTAL

3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.

Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

Interventions

Pregnenolone 500 mg DRUG

Pregnenolone 500 mg capsule.

Also known as: Neurosteroid

Placebo > Pregnenolone 500 > Pregnenolone 800; Placebo > Pregnenolone 800 > Pregnenolone 500; Pregnenolone 500 > Placebo > Pregnenolone 800; Pregnenolone 500 > Pregnenolone 800 > Placebo; Pregnenolone 800 > Placebo > Pregnenolone 500; Pregnenolone 800 > Pregnenolone 500 > Placebo

Pregnenolone 800 mg DRUG

Pregnenolone 800 mg capsule.

Also known as: Neurosteroid

Placebo > Pregnenolone 500 > Pregnenolone 800; Placebo > Pregnenolone 800 > Pregnenolone 500; Pregnenolone 500 > Placebo > Pregnenolone 800; Pregnenolone 500 > Pregnenolone 800 > Placebo; Pregnenolone 800 > Placebo > Pregnenolone 500; Pregnenolone 800 > Pregnenolone 500 > Placebo

Placebo DRUG

Placebo capsule manufactured to mimic pregnenolone capsule.

Placebo > Pregnenolone 500 > Pregnenolone 800; Placebo > Pregnenolone 800 > Pregnenolone 500; Pregnenolone 500 > Placebo > Pregnenolone 800; Pregnenolone 500 > Pregnenolone 800 > Placebo; Pregnenolone 800 > Placebo > Pregnenolone 500; Pregnenolone 800 > Pregnenolone 500 > Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women, ages 18-65 years, with current MDD (mild or moderate severity per DSM-5) based on SCID-CV.
• No psychotropic medications, other than PRN (as needed) hypnotics, within 28 days of randomization (medication free).
• PRN hypnotics allowed up to 3 days prior to study drug administrations but not while receiving study drug.

You may not qualify if:

• Severe MDD based on DSM-5 severity criteria and/or a baseline HRSD score \> 27 (consistent with severe depressive symptom severity).
• High risk for suicide (active SI with plan/intent or \> 2 lifetime attempts in lifetime or any in the past 6 months).
• Treatment resistant depression (fail two adequate antidepressant trials or ECT during current episode).
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated).
• Coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder, or any severe, life threatening or unstable, medical condition.
• History of allergic reaction or side effects with prior pregnenolone use.
• Current substance use disorder defined as meeting criteria for a use disorder based on the SCID interview and self-reported use within the past 3 months, or a positive baseline urine drug screen.
• Current psychotic features (hallucinations, delusions, disorganized thought processes) or eating disorders.
• Anxiety disorders of sufficient severity to be the primary focus of clinical attention (e.g. severe obsessive compulsive or post-traumatic stress disorders).
• Hormone-sensitive conditions (i.e. breast cancer; uterine/ovarian cancer, endometriosis, uterine fibroids).
• Clinically significant laboratory, physical examination, or electrocardiogram (ECG) findings.
• Currently using oral contraceptives containing progestin (barrier methods allowed).

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• National Center for Complementary and Integrative Health (NCCIH): collaborator

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Pregnenolone; Neurosteroids

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs

Limitations and Caveats

Some fMRI data may have been excluded as a result of motion in the MRI machine.

Results Point of Contact

• Title: Dr. Sherwood Brown
• Organization: UT Southwestern Medical Center

Sherwood.Brown@utsouthwestern.edu

214-645-6950

Study Officials

• Sherwood Brown, MD, PhD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Adult women with mild to moderate major depressive disorder (MDD) will receive pregnenolone (500 mg/d, 800 mg/d and placebo) in a randomized, double-blind, crossover design.

Study Record Dates

• First Submitted: August 22, 2018
• First Posted: August 24, 2018
• Study Start: September 1, 2019
• Primary Completion: May 31, 2022
• Study Completion: May 31, 2022
• Last Updated: May 1, 2024
• Results First Posted: May 1, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)