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Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-Withdrawal-Induced Mood Symptoms in Women With Past Perimenopausal Depression

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ClinicalTrials.gov Identifier: NCT03689543
Recruitment Status : Recruiting
First Posted : September 28, 2018
Last Update Posted : May 8, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Tracking Information
First Submitted Date  ICMJE September 26, 2018
First Posted Date  ICMJE September 28, 2018
Last Update Posted Date May 8, 2020
Actual Study Start Date  ICMJE May 23, 2019
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2019)
  • Epidemiologic Studies-Depression Scale (CES-D) [ Time Frame: Ongoing ]
    Epidemiologic Studies-Depression Scale (CES-D)
  • bserver ratings - the 17-item Hamilton Rating Scale of Depression(HRSD) [ Time Frame: Ongoing ]
    bserver ratings - the 17-item Hamilton Rating Scale of Depression(HRSD)
Original Primary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
  • Epidemiologic Studies-Depression Scale (CES-D) [ Time Frame: Ongoing ]
  • bserver ratings - the 17-item Hamilton Rating Scale of Depression(HRSD) [ Time Frame: Ongoing ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
  • endometrial thickness as measured by vaginal ultrasound [ Time Frame: ongoing ]
  • Plasma LH, FSH, prolactin, and lipid levels [ Time Frame: Ongoing ]
  • Visual analogue scale (VAS) [ Time Frame: Ongoing ]
  • Beck Depression Inventory (BDI) [ Time Frame: Ongoing ]
  • 14 item six point likert-type scale [ Time Frame: Ongoing ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-Withdrawal-Induced Mood Symptoms in Women With Past Perimenopausal Depression
Official Title  ICMJE The Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-withdrawal-induced Mood Symptoms in Women With Past Perimenopausal Depression.
Brief Summary

Background:

Some women who had depression in the perimenopause may have mood symptoms again if they stop estrogen therapy. Estrogen acts in the brain and other tissues by binding to at least three types of estrogen receptors. One of these receptors, estrogen receptor beta may affect anxiety and depression. The drug LY500307 acts only on this receptor. In this study, researchers will initially give you estrogen and then suddenly stop estrogen after three weeks. Then they will study how LY500307 affects mood symptoms.

Objectives:

To study how withdrawing estradiol affects mood. To test the safety and side effects of LY500307.

Eligibility:

Healthy women ages 45-65 who had depression related to perimenopause in recent years and whose mood systems got better with estradiol

Design:

-Participants will be screened with:

Medical history

Physical exam

Blood tests

Psychiatric interview

Gynecological exam

  • Participants able to get pregnant must use effective barrier birth control throughout the study.
  • During the first 3 weeks, participants will wear an estrogen patch. It is 1x2 inches and will be replaced every 3 days.
  • For the next 3 weeks, participants will take 3 study capsules every morning. They will not know if they get the study drug or placebo.
  • Some participants will also take a progesterone-like drug for 1 week at the end of the medication phase of the study.
  • Participants will have 9 one-hour study visits. They will have blood samples and vital signs taken. They will answer questions about mood and behavior symptoms.
  • Participants will keep a daily log of these symptoms.
  • Participants will have 2 transvaginal ultrasounds. A probe is temporarily placed 2-3 inches into the vaginal canal and sound waves are used to create pictures of the lining of the uturus.
  • Participants will have a final visit 4 weeks after stopping the study drug. They will answer questions about mood and side effects.
Detailed Description

OBJECTIVE:

During the perimenopause, the incidence of depression increases 1-5 and predicts increased all-cause and cardiovascular mortality. A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by estradiol s antidepressant efficacy and safety in perimenopausal depression. Moreover, observational studies report the emergence of depressive symptoms after the discontinuation of menopausal hormone therapy (HT) in 5-10% of women. The coincidence of declining ovarian function with the onset of depression led to the inference that withdrawal from physiologic estradiol levels underpinned depression during the perimenopause. To test this inference, we undertook a study to examine the role of estradiol withdrawal in perimenopausal depression. We evaluated the effects of the acute withdrawal of estradiol therapy in postmenopausal women with and those without a past perimenopausal depression. Results demonstrated that estradiol withdrawal induces depressive symptoms in women with a past perimenopausal depression, but not in those without such a history. This study was the first to provide direct evidence that estradiol withdrawal is the relevant physiologic trigger for depressive symptoms in women with this condition. In women with past perimenopausal depression, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. These data also suggest that the effects of estradiol withdrawal are processed differently in some women, presumably by altering the brain network composition or activity that underlies affective state. In this next protocol, we will examine a possible mechanism mediating the effects of estradiol- withdrawal on mood symptoms in asymptomatic postmenopausal women with a past perimenopausal depression. We propose to evaluate the efficacy and safety of a selective estrogen receptor (ER) beta agonist (Lilly Compound LY500307) to prevent estradiol withdrawal-induced mood symptoms. The effects of estradiol primarily occur through activation of two receptor subtypes, often with opposing outcomes: estrogen receptor (ER) alpha, and ER beta. We focus on ER beta because the beta estrogen receptor is reported to mediate the effects of estradiol on the serotonergic system and mediate the antidepressant-like effects of estradiol in the forced-swim test. Moreover, selective agonists of estrogen receptor beta have been demonstrated to attenuate the behavioral and hypothalamic-pituitary- adrenal (HPA) axis response to stress in animal studies. We propose to employ the selective estrogen receptor agonist LY500307 under double-blind, placebo controlled conditions to examine the specific role of estrogen receptor beta in the effects of estrogen withdrawal in women with a past perimenopause-related depression. Depressive symptoms will be measured with standardized ratings scales (i.e., Center for Epidemiologic Studies Depression scale (CES-D) and 17-item Hamilton Rating Scale of Depression (HRSD)). Results of this study will determine the role of ER beta in estradiol withdrawal-induced mood symptoms and can provide preliminary data to support the efficacy and safety of this compound as a treatment for depression during the perimenopausal transition.

STUDY POPULATION:

We propose to employ the selective estrogen receptor agonist LY500307 under double-blind, placebo controlled conditions to examine the specific role of estrogen receptor beta in the effects of estrogen withdrawal in women with a past perimenopause-related depression. Depressive symptoms will be measured with standardized ratings scales (i.e., Center for Epidemiologic Studies Depression scale (CES-D) and 17-item Hamilton Rating Scale of Depression (HRSD)). Results of this study will determine the role of ER beta in estradiol withdrawal-induced mood symptoms and can provide preliminary data to support the efficacy and safety of this compound as a treatment for depression during the perimenopausal.

DESIGN:

We propose to employ the selective estrogen receptor agonist LY500307 under double-blind, placebo controlled conditions to examine the specific role of estrogen receptor beta in the effects of estrogen withdrawal in women with a past perimenopause-related depression. Depressive symptoms will be measured with standardized ratings scales (i.e., Center for Epidemiologic Studies Depression scale (CES-D) and 17-item Hamilton Rating Scale of Depression (HRSD)). Results of this study will determine the role of ER beta in estradiol withdrawal-induced mood symptoms and can provide preliminary data to support the efficacy and safety of this compound as a treatment for depression during the perimenopausal.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Perimenopausal Depression
Intervention  ICMJE
  • Drug: ER beta agonist
    Lilly Compound LY500307
  • Other: Placebo
    Placebo
Study Arms  ICMJE
  • Experimental: Arm 1
    all women receive open label (OL) estradiol therapy (ET) at a dose of 100 micrograms per day bytransdermal skin patch
    Intervention: Drug: ER beta agonist
  • Experimental: Arm 2
    all women receive three weeks of double blind (DB) medication (i.e., LY500307 [at a daily dose of either 25 mg or 75 mg] or placebo)
    Intervention: Drug: ER beta agonist
  • Placebo Comparator: Arm 3
    Matched placebo
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 27, 2018)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2024
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

    1. Women with a past perimenopause-related depression (within 12 years). The diagnosis of perimenopause-related depression will be based on a history of a past depressive episode (major or minor depression confirmed by Structured Clinical Interview for DSM-V (SCID)) at midlife in association with menstrual cycle irregularity (and possibly hot flushes and/or vaginal dryness) and in whom menopausal hormone therapy was reported to improve their depression at any time within the prior twelve years. All women participating in this protocol will have previously completed the screening protocol # 88-M-0131 during which psychiatric, medical, and reproductive evaluations will be performed and they will have been confirmed to be in good medical health.
    2. Age 45 to 65
    3. Medication free (including no mood stabilizers, no sleep medication) except for the following: women on menopausal hormone therapy who will discontinue these medications at the start of this study and have their hormone therapy replaced with estradiol 100mcg per day (as described below), women who are on stable doses of thyroid replacement for at least six months prior to study enrollment, or women who occasionally take non-steroidal anti-inflammatory drugs [NSAIDs] or allergy medications (although we will ask women to minimize the use of these medications during the study).
    4. Subjects must have consent capacity

EXCLUSION CRITERIA:

The following conditions will constitute contraindications to participate in this protocol:

  1. Any current Axis 1 psychiatric illness or any clinically significant sleep disorder;
  2. Women with histories of hormone replacement therapy-induced dysphoria due to either the estrogen or the progesterone components of their hormone replacement;
  3. Past history of major depression with suicidal ideation;
  4. History of ischemic cardiac disease, pulmonary embolism, or thrombophlebitis;
  5. Renal disease; hepatic dysfunction; history of cholecystitis; hypertension;
  6. Women with a history of carcinoma of the breast or any undiagnosed breast nodule/mass;
  7. Women with a history of uterine cancer, ill-defined pelvic lesions, particularly undiagnosed ovarian enlargement, undiagnosed vaginal bleeding;
  8. Pregnant women; sexually active women will be required to employ barrier contraceptive methods;
  9. Cerebrovascular disease (stroke);
  10. Recurrent migraine headaches;
  11. Women who have had a hysterectomy before one year after their last menstrual period.

NIMH employees/staff and their immediate family members will be excluded from the study per NIMH policy.

Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 45 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Peter J Schmidt, M.D. (301) 496-6120 peterschmidt@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03689543
Other Study ID Numbers  ICMJE 180144
18-M-0144
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
Study Sponsor  ICMJE National Institute of Mental Health (NIMH)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Peter J Schmidt, M.D. National Institute of Mental Health (NIMH)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date May 5, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP