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| ID | Type | Description | Link |
|---|---|---|---|
| 1R61AT009625-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Center for Complementary and Integrative Health (NCCIH) | NIH |
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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.
In this study, 26 adult women meeting criteria for Major Depressive Disorder (MDD) as defined in DSM 5, will be randomized to a double-blind, placebo-controlled, crossover phase I clinical trial of pregnenolone (i.e. each participant receives 500 mg/d, 800 mg/d pregnenolone and placebo in random order). The study will consist of three 7-day treatment exposures to each pregnenolone dose with a 14-day washout between each exposure. Baseline evaluation will include medical and psychiatric history, psychiatric interview, standard laboratory analyses (i.e., blood draw, ECG), and a brief cognitive battery. Neuroimaging will be collected after each study drug or placebo administration. Study drug tolerability and participant safety will be assessed throughout the study (6 in-clinic visits + a safety visit) using structured clinical interviews, self-report questionnaires, and standard laboratory analyses.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pregnenolone 500 > Pregnenolone 800 > Placebo | Experimental | 3 exposures in order:
|
|
| Pregnenolone 500 > Placebo > Pregnenolone 800 | Experimental | 3 exposures in order:
|
|
| Pregnenolone 800 > Pregnenolone 500 > Placebo | Experimental | 3 exposures in order:
|
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| Pregnenolone 800 > Placebo > Pregnenolone 500 | Experimental | 3 exposures in order:
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pregnenolone 500 mg | Drug | Pregnenolone 500 mg capsule. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Pregnenolone Level | Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum pregnenolone levels are indicative of bioavailability. | 7 days |
| Allopregnanolone Level |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sherwood Brown, MD, PhD | University of Texas Southwestern Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UT Southwestern Medical Center | Dallas | Texas | 75390 | United States |
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29 of 34 participants were randomized. It was determined that 5 subjects were not eligible for the study and were not randomized.
Subjects were screened for eligibility from September 2019 through November 2021 at UT Southwestern in Dallas, TX. 34 Subjects were consented by a research study coordinator in a private office within Dr. Brown's PNE Lab.
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| ID | Title | Description |
|---|---|---|
| FG000 | Pregnenolone 500 > Pregnenolone 800 > Placebo | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| FG001 | Pregnenolone 500 > Placebo > Pregnenolone 800 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| FG002 | Pregnenolone 800 > Pregnenolone 500 > Placebo | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| FG003 | Pregnenolone 800 > Placebo > Pregnenolone 500 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| FG004 | Placebo > Pregnenolone 500 > Pregnenolone 800 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| FG005 | Placebo > Pregnenolone 800 > Pregnenolone 500 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Treatment (21 Days) |
| |||||||||||||
| Second Treatment (21 Days) |
| |||||||||||||
| Third Treatment (21 Days) |
|
The overall number of baseline participants does not differ from the number of participants randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | Pregnenolone 500 > Pregnenolone 800 > Placebo | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Some fMRI data may have been unusable due to motion in the scanner. | Posted | Mean | Standard Deviation | z-score | 7 days |
|
AEs were collected over a 2+ year period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pregnenolone 800 | Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. |
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Some fMRI data may have been excluded as a result of motion in the MRI machine.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Sherwood Brown | UT Southwestern Medical Center | 214-645-6950 | Sherwood.Brown@utsouthwestern.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 9, 2020 | Aug 24, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| D003863 | Depression |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D001526 | Behavioral Symptoms |
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| ID | Term |
|---|---|
| D011284 | Pregnenolone |
| D000081227 | Neurosteroids |
| ID | Term |
|---|---|
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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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.
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|
| Placebo > Pregnenolone 500 > Pregnenolone 800 | Experimental | 3 exposures in order:
|
|
| Placebo > Pregnenolone 800 > Pregnenolone 500 | Experimental | 3 exposures in order:
|
|
|
| Pregnenolone 800 mg | Drug | Pregnenolone 800 mg capsule. |
|
|
| Placebo | Drug | Placebo capsule manufactured to mimic pregnenolone capsule. |
|
Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum allopregnanolone levels are indicative of bioavailability. |
| 7 days |
| Systematic Assessment for Treatment Emergent Events (SAFTEE) | Assess safety and tolerability of pregnenolone at the doses tested. SAFTEE is a side effect self-report assessment scale that consists of 56 potential side effects. Participants rate how bothersome each side effect is on a scale of "none" (0), "mild" (1), "moderate" (2), "severe" (3). Total scores range from 0 to 168. A higher total score (sum of all items) indicates a higher level of side effect burden. | 7 days |
| Pregnenolone Dose | Identify a dose of pregnenolone that demonstrates bioavailability (see "Pregnenolone Level" and "Allopregnanolone Level" outcome measures), tolerability (see "SAFTEE" outcome measure); and is associated with a significant change in a biosignature. | 7 days |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | Pregnenolone 500 > Placebo > Pregnenolone 800 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| BG002 | Pregnenolone 800 > Pregnenolone 500 > Placebo | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| BG003 | Pregnenolone 800 > Placebo > Pregnenolone 500 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| BG004 | Placebo > Pregnenolone 500 > Pregnenolone 800 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| BG005 | Placebo > Pregnenolone 800 > Pregnenolone 500 | 3 exposures in order:
Pregnenolone 500 mg: Pregnenolone 500 mg capsule. Pregnenolone 800 mg: Pregnenolone 800 mg capsule. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. |
| BG006 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| HAM-D | The Hamilton Rating Scale for Depression (HAM-D) is a 17-item instrument to assess depressive symptom severity. Each item represents a depressive symptom and is scored on a 5-point Likert scale with 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = incapacitating. Item scores are summed to derive a total score ranging from 0-68. Higher total scores indicate greater depressive symptom severity. | Mean | Standard Deviation | units on a scale |
|
| OG001 | Pregnenolone (800 mg) | Pregnenolone 800 mg capsule by mouth, daily for 7 days. |
| OG002 | Placebo | Matching placebo capsule by mouth, daily for 7 days. |
|
|
|
| Primary | 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). | Some fMRI data may have been unusable due to motion in the scanner. | Posted | Mean | Standard Deviation | z-score | 7 days |
|
|
|
|
| Primary | 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. | All participants with available data for each treatment condition. | Posted | Mean | Standard Deviation | millimolars (mM) | 7 days |
|
|
|
|
| Secondary | Pregnenolone Level | Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum pregnenolone levels are indicative of bioavailability. | All participants with available data for each treatment condition. | Posted | Mean | Standard Deviation | pg/mL | 7 days |
|
|
|
|
| Secondary | Allopregnanolone Level | Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum allopregnanolone levels are indicative of bioavailability. | All participants with available data for each treatment condition. | Posted | Mean | Standard Deviation | pg/mL | 7 days |
|
|
|
|
| Secondary | Systematic Assessment for Treatment Emergent Events (SAFTEE) | Assess safety and tolerability of pregnenolone at the doses tested. SAFTEE is a side effect self-report assessment scale that consists of 56 potential side effects. Participants rate how bothersome each side effect is on a scale of "none" (0), "mild" (1), "moderate" (2), "severe" (3). Total scores range from 0 to 168. A higher total score (sum of all items) indicates a higher level of side effect burden. | All participants with available data for each treatment condition. | Posted | Mean | Standard Deviation | units on a scale | 7 days |
|
|
|
|
| Secondary | Pregnenolone Dose | Identify a dose of pregnenolone that demonstrates bioavailability (see "Pregnenolone Level" and "Allopregnanolone Level" outcome measures), tolerability (see "SAFTEE" outcome measure); and is associated with a significant change in a biosignature. | Posted | Number | mg | 7 days |
|
|
|
| 0 |
| 29 |
| 0 |
| 29 |
| 0 |
| 29 |
| EG001 | Pregnenolone 500 | Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. Pregnenolone 500 mg: Pregnenolone 500 mg capsule. | 0 | 29 | 0 | 29 | 0 | 29 |
| EG002 | Placebo | Matching placebo capsule by mouth, daily for 7 days. Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. | 0 | 29 | 0 | 29 | 0 | 29 |
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| D001519 |
| Behavior |
| D011083 |
| Polycyclic Compounds |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045167 | Progesterone Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D018377 | Neurotransmitter Agents |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D045505 | Physiological Effects of Drugs |
| Superiority |
| Null Hypothesis: dlPFC-Insula functional connectivity (z-score) at 800 mg will be less than or equal to that at placebo. Alternative Hypothesis: dlPFC-Insula functional connectivity (z-score) at 800 mg will be greater than that at placebo. | t-test, 1 sided | Paired samples t-test with corrected standard deviation of the difference. | .458 | Statistical significance is evaluated at p (one-tailed) <= .05. | Mean Difference (Final Values) | 0.0097 | Standard Error of the Mean | 0.0891 | 2-Sided | 95 | -0.1803 | 0.1996 | Mean Difference = placebo - pregnenolone (800 mg) | Superiority |
| Superiority |
| Null Hypothesis: GABA concentration (mM) at 500 mg will be less than or equal to that at placebo. Alternative Hypothesis: GABA concentration (mM) at 500 mg will be greater than that at placebo. | t-test, 1 sided | Paired samples t-test with corrected standard deviation of the difference. | .071 | Statistical significance is evaluated at p (one-tailed) <= .05. | Mean Difference (Final Values) | 0.0131 | Standard Error of the Mean | 0.0084 | 2-Sided | 95 | -0.0050 | 0.0312 | Mean Difference = placebo - pregnenolone (800 mg) | Superiority |
| Superiority |
| Null Hypothesis: Pregnenolone level (pg/mL) at 800 mg will be less than or equal to that at placebo. Alternative Hypothesis: Pregnenolone level (pg/mL) at 800 mg will be greater than that at placebo. | t-test, 1 sided | Paired samples t-test with corrected standard deviation of the difference. | .003 | Statistical significance is evaluated at p (one-tailed) <= .05. | Mean Difference (Final Values) | -11828.78 | Standard Error of the Mean | 3620.42 | 2-Sided | 95 | -19650.24 | -4007.33 | Mean Difference = placebo - pregnenolone (800 mg) | Superiority |
| Superiority |
| Null Hypothesis: Allopregnanolone level (pg/mL) at 800 mg will be less than or equal to that at placebo. Alternative Hypothesis: Allopregnanolone level (pg/mL) at 800 mg will be greater than that at placebo. | t-test, 1 sided | Paired samples t-test with corrected standard deviation of the difference. | .001 | Statistical significance is evaluated at p (one-tailed) <= .05. | Mean Difference (Final Values) | -2480.62 | Standard Error of the Mean | 582.63 | 2-Sided | 95 | -3739.32 | -1221.93 | Mean Difference = placebo - pregnenolone (800 mg) | Superiority |
Using the two one-sided test (TOST) procedure (Schuirmann, 1987), equivalence is established at the α significance level if a (1-2α) × 100% confidence interval for the difference in efficacies (new - current) is contained within the interval (-δ, δ) Schuirmann, D. J. (1987). A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. Journal of pharmacokinetics and biopharmaceutics, 15, 657-680. |
| Null Hypothesis: SAFTEE (total) scores at 800 mg will be greater than or equal to that at placebo. Alternative Hypothesis: SAFTEE (total) scores at 800 mg will be less than that at placebo. | t-test, 1 sided | Paired samples t-test with corrected standard deviation of the difference. | .240 | Statistical significance is evaluated at p (one-tailed) <= .05. | Mean Difference (Final Values) | -2.5000 | Standard Error of the Mean | 3.4662 | 2-Sided | 95 | -9.8131 | 4.8131 | Mean Difference = placebo - pregnenolone (800 mg) | Non-Inferiority | Using the two one-sided test (TOST) procedure (Schuirmann, 1987), equivalence is established at the α significance level if a (1-2α) × 100% confidence interval for the difference in efficacies (new - current) is contained within the interval (-δ, δ) Schuirmann, D. J. (1987). A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. Journal of pharmacokinetics and biopharmaceutics, 15, 657-680. |