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A Neurosteroid Intervention for Menopausal and Perimenopausal Depression

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ClinicalTrials.gov Identifier: NCT03505905
Recruitment Status : Recruiting
First Posted : April 23, 2018
Last Update Posted : September 26, 2018
Sponsor:
Collaborator:
Massachusetts General Hospital
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Brief Summary:

HYPOTHESIS:

Pregnenolone administration will be associated with greater reduction in depressive symptom severity than placebo in women with current mMDD.

STUDY AIMS:

Primary Aim: Determine if pregnenolone is associated with greater reduction in depressive symptom severity than placebo in women with mMDD, as measured by MADRS.

Secondary Aims:

  1. Determine if pregnenolone is associated with greater reduction in anxiety symptom severity than placebo in women with mMDD.
  2. Determine if pregnenolone is associated with greater improvement in cognition than placebo in women with mMDD.
  3. Determine if pregnenolone is associated with greater improvement in quality of life than placebo in women with mMDD.
  4. Determine if pregnenolone is associated with greater improvement in vasomotor symptoms of menopause than placebo.

Mechanistic Aims:

  1. Determine whether changes in neurosteroid levels with pregnenolone mediate clinical response.
  2. Determine if baseline neurosteroid levels predict pregnenolone response.
  3. Determine whether depressive symptoms, anxiety, sleep or vasomotor symptoms improve first. A crossed-lagged panel model will explore serial correlations between changes in outcome measures.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Menopause Perimenopause Drug: Pregnenolone Drug: Placebo Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: A double-blind, placebo-controlled, Sequential Parallel Comparison Design (SPCD) trial of pregnenolone. SPCD is a clinical trial design that may reduce the effect of placebo response on signal detection and maximize the ability to assess efficacy by dividing the trial into two phases, and then re-randomizing placebo non-responders.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Neurosteroid Intervention for Menopausal and Perimenopausal Depression
Actual Study Start Date : September 1, 2018
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anxiety Menopause

Arm Intervention/treatment
Experimental: Pregnenlone (phase 1 and 2)
Participants will receive pregnenolone at phase 1 (baseline-WK 7) and 2 (WK 8-16). The titration schedule is as follows: at baseline a 50 mg (BID, 7 days). WK 1=150 mg (BID, 7 days); WK 2=250 mg (BID, 14 days) and WK 4=250 mg (BID, 14 days) (BID, 14 days). At phase 2 (WK 8) to maintain the double blind of rerandomization, treatment in all conditions recommence at a dosage frequency similar to phase 1. At WK 8=250 mg (BID, 7 days); at WK 9=250 mg (BID, 7 days); WK 10=250 mg (BID, 14 days) and WK 12=250 mg (BID, 14 days) . During the participants' final WK (16), they will be instructed to titrate down the treatment according to the following schedule: 150 mg (BID, 4 days) and 50 mg (BID, 4 days), discontinue.
Drug: Pregnenolone
In a sequential parallel comparison design, in a double blind placebo controlled study, the efficacy of pregnenlone treatment relative to placebo in improving depression and anxiety symptoms, cognition, sleep, quality of life and vasomotor symptoms in preimenopausal and menopausal women with MDD.

Placebo Comparator: Placebo rerandom to placebo
Participants will receive placebo at phase 1 (baseline-WK 7) & treatment response assessed (MADRS score reduced <50% at WK8). Nonresponders are rerandomized to receive either treatment at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1= placebo (7 days); at WK 2=placebo (14 days) and WK 4=placebo (14 days). Placebo nonresponders rerandomized to placebo: At WK 8=placebo (7 days);WK 9=placebo (7 days);WK 10=placebo (14 days) and WK 12=placebo (14 days). During the participants' final WK (16), they will be instructed to titrate down (done in order to maintain the double blind) the treatment according to the following schedule: placebo (4 days) and placebo (4 days), discontinue.
Drug: Placebo
In a sequential parallel comparison design, in a double blind placebo controlled study, the efficacy of pregnenlone treatment relative to placebo in improving depression and anxiety symptoms, cognition, sleep, quality of life and vasomotor symptoms in preimenopausal and menopausal women with MDD.

Experimental: Placebo rerandom to pregnenolone
Participants will receive placebo at phase 1 (baseline-WK 7) & treatment response assessed (MADRS score reduced <50% at WK8). Nonresponders are rerandomized to receive either treatment at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1=placebo (7 days); WK 2=placebo (14 days) & WK 4=placebo (14 days). Placebo nonresponders who are rerandomized to pregnenolone: At WK 8=250 mg (7 days);WK 9=250 mg (7 days);WK 10=250 mg (14 days) & WK 12=250 mg (14 days). During the participants' final WK (16), they will be instructed to titrate down the treatment according to the following schedule: 150 mg (4 days) and 50 mg (4 days), discontinue.
Drug: Pregnenolone
In a sequential parallel comparison design, in a double blind placebo controlled study, the efficacy of pregnenlone treatment relative to placebo in improving depression and anxiety symptoms, cognition, sleep, quality of life and vasomotor symptoms in preimenopausal and menopausal women with MDD.

Drug: Placebo
In a sequential parallel comparison design, in a double blind placebo controlled study, the efficacy of pregnenlone treatment relative to placebo in improving depression and anxiety symptoms, cognition, sleep, quality of life and vasomotor symptoms in preimenopausal and menopausal women with MDD.

Placebo Comparator: Placebo responsive cont placebo
Participants will placebo throughout phase 1 (baseline- WK 7) & treatment response assessed (MADRS score reduced <50% at WK8). Responders continue to receive placebo at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1=placebo (7 days); WK 2=placebo (14 days) & WK 4=placebo (14 days). Placebo responders remain on placebo: At WK 8, placebo (7 days); WK 9=placebo (7 days); WK 10=placebo (14 days) & WK 12=placebo (14 days). During the participants' final WK (16), they will be instructed to titrate down (done in order to maintain the double blind) the treatment according to the following schedule: placebo= 4 days) and placebo=4 days, discontinue.
Drug: Placebo
In a sequential parallel comparison design, in a double blind placebo controlled study, the efficacy of pregnenlone treatment relative to placebo in improving depression and anxiety symptoms, cognition, sleep, quality of life and vasomotor symptoms in preimenopausal and menopausal women with MDD.




Primary Outcome Measures :
  1. Montgomery-Asberg Depression Rating Scale (MADRS) [ Time Frame: 16 weeks ]
    Depression; MADRS (primary outcome) is an observer-rated 10-item measure of depressive symptomatology designed for use in clinical trials. Each item is rated from 0-6 in order of increasing severity based upon the assessment of symptoms within the past 7 days. The range of total scores is 0-60, with higher score indicative of more severe depressive symptoms.


Secondary Outcome Measures :
  1. Hamilton Anxiety Rating Scale (HRSA) [ Time Frame: 16 Weeks ]
    Anxiety assessment (secondary outcome) is an 14-item observer-rated scale that assesses the degree and pathology associated with anxiety such as anxious mood, tension, fear, and insomnia

  2. Pittsburgh Sleep Quality Index (PSQI) [ Time Frame: 16 Weeks ]
    Quality of life: (secondary outcome) is an 9-item self-report scale used to assess sleep quality and disturbances during the past week

  3. Menopause Specific Quality of Life (MEN-QOL) [ Time Frame: 16 weeks ]
    Menopause Vasomotor Symptoms (secondary outcome) is an 29-item measure used to assess the presence and bother associated with 29-different menopausal symptoms

  4. Greene Climacteric Scale (GCS) [ Time Frame: 16 weeks ]
    Menopause Symptoms (secondary outcome) is an 21-item checklist providing an objective measure of mood disturbance, hot flushes, night sweats, and vaginal dryness

  5. Rey Auditory Verbal Learning Test (RAVLT) [ Time Frame: 16 Weeks ]
    Assess changes in cognition: is an auditory assessment of verbal learning and memory, in which the participant is asked to recall a list of words first immediately following presentation (immediate recall) and later following a set period of time (delayed recall)

  6. Trail Making Test (TMT) [ Time Frame: 16 Weeks ]
    Assess changes in cognition: is an diagnostic tool measuring executive functioning and information processing in which the participant is asked to link a set of randomly distributed numbered and lettered points


Other Outcome Measures:
  1. Blood drawn [ Time Frame: 16 weeks ]
    changes in neurosteroid levels-CBC,CMP, Neurosteroid levels

  2. Systematic Assessment for Treatment Emergent Events (SAFTEE) [ Time Frame: 16 weeks ]
    safety and tolerability data- is an 56-item self-report checklist used to assess study drug side effects and tolerability

  3. Cognitive and Physical Functioning Questionnaire (CPFQ) [ Time Frame: 16 weeks ]
    safety and tolerability data-is an 7-item self-report questionnaire that assesses possible cognitive and physical side effects

  4. Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: 16 weeks ]
    safety and tolerability data-is anobserver-rated measure for assessing suicidal ideation and risk in clinical trials. C-SSRS consists of subscales assessing severity of ideation, intensity of ideation, suicidal behavioral, and lethality



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Ages Eligible for Study:   40 Years to 62 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

The participants must meet the following criteria:

  • Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years of the last menstrual period if not surgically postmenopausal), including:
  • Women who have experienced changes in menstrual cycle frequency or duration, and/or physical symptoms indicative of menopausal transition, as determined by clinician
  • Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level > 20 mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making irregular/absent periods difficult to assess as related to the menopausal transition).
  • Women with significant menopause-related physical symptoms, indicated by any of the following criteria:
  • Greene Climacteric Scale total scores > 20
  • Greene Climacteric Scale sub-score for vasomotor symptoms >3
  • 5 or more bothersome hot flashes per week (self-reported)
  • Women meeting DSM-5 criteria for current major depressive disorder (assessed by the SCID)
  • Baseline HRSD score of ≥ 18
  • Subject agrees to abstain from disallowed medications for the duration of the trial

Exclusion Criteria:

The participants must not meet any of the following criteria:

  • Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
  • Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding
  • Psychiatric disorder other than MDD that is acute and the primary focus of symptom burden or treatment.
  • History of bipolar disorder or psychotic disorder
  • Current substance use disorder
  • Positive baseline urine drug screen of an illicit substance with the exception of a medication used with a prescription such as an opioid pain medication
  • Current eating disorder
  • Treatment resistant depression (failure of 2 adequate antidepressant trials or electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials are defined as within the US FDA approved dosage for the medication and used for at least 6 weeks, with failure described by the patient as <50% improvement based on her subjective experience). )
  • High risk for suicidal acts including active suicidal ideation with plan and intent or > 2 suicide attempts in lifetime or any attempt in the past 6 months
  • Women who have used psychoactive or centrally acting medications within 2 weeks prior to study screening
  • Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpiderm, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed), and antidepressants within 2 weeks of the baseline visit and randomization.
  • Use of natural menopause and depression supplements, phytoestrogens, soy-based medications, steroids within 2 weeks of baseline visit and randomization.
  • Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), natural menopause supplements, episodic sleep medications (chronic, regular, stable-dose benzodiazepines allowed), antidepressants, phytoestrogens, soy-based medications, steroids within 4 weeks of randomization
  • Use of any disallowed medications (specified in the Excluded Concomitant Medication section below)
  • Women who have received a gonadal hormonal intervention within 1 month prior to study entry (stable thyroid medications are allowed).
  • Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period (IUDs, condoms, abstinence are acceptable forms of contraception in this study; due to the possible interactions with the study medication, oral contraceptive pills will be prohibited)
  • Uncontrolled hypertension (>160/95mmHg)
  • Active Coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder
  • Any severe, life threatening or unstable medical condition that, based on clinician-judgment, would make participation in the study unsafe or inappropriate
  • Personal or first- degree family history of known hormone sensitive tumors
  • History of allergic reaction or side effects with prior pregnenolone use
  • Clinically significant laboratory, physical examination
  • Concurrent enrollment in another clinical trial

Exclusion of Concomitant Medications:

  • Selective estrogen-receptor modulators (SERMs)
  • Hormone replacement therapy
  • Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone
  • Natural menopause or antidepressant supplements
  • Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed)
  • Antidepressants used at indicated, therapeutic, FDA-approved doses (Note: sub-therapeutic dosages of antidepressants used for other indications will be permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin).
  • Phytoestrogens
  • Soy-based medications or supplements

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03505905


Contacts
Contact: Stephanie Reyes 214-645-6953 stephanie.reyes@utsouthwestern.edu
Contact: Alexandra Kulikova 214-645-6967 alexandra.kulikova@utsouthwestern.edu

Locations
United States, Texas
UT Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Stephanie Reyes       stephanie.reyes@utsouthwestern.edu   
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Massachusetts General Hospital
Investigators
Principal Investigator: Sherwood Brown, MD, PhD UT Southwestern Medical Center
Principal Investigator: Marlene Freeman, MD Massachusetts General Hospital

Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT03505905     History of Changes
Other Study ID Numbers: 102017-068
First Posted: April 23, 2018    Key Record Dates
Last Update Posted: September 26, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Texas Southwestern Medical Center:
Pregnenolone

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs