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Unique Effects of Perimenstrual Estradiol or Progesterone Supplementation on Perimenstrual Suicidality (CLEAR-2)

Primary Purpose

Suicidal Ideation

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Transdermal Estradiol + Placebo
Oral Micronized Progesterone + Placebo
Placebos
Sponsored by
University of Illinois at Chicago
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Suicidal Ideation focused on measuring steroid hormones, estradiol, estrogen, progesterone, depression, suicide

Eligibility Criteria

18 Years - 45 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Ability to adhere to medication regimen
  • Speaks English
  • Assigned female at birth with intact ovaries
  • Premenopausal
  • Normal menstrual cycles between 25-35 days
  • Under current care of an outpatient mental health provider with visits occurring at least once every 3 months.
  • At least 1 year postpartum.
  • Willing to use a barrier method of birth control during the study.
  • Normal weight (BMI between 18.00-29.99)
  • Must report at least some recent suicidal ideation (in the past month) at the time of recruitment.
  • Must be categorized as having acceptably low imminent risk for suicidal crisis/attempt by a licensed clinical psychologist utilizing evidence-based clinical and research guidelines for imminent suicide risk management.

Exclusion Criteria:

  • Must not be pregnant, breastfeeding, or trying to become pregnant.
  • Must not be taking any form of exogenous hormones or hormonal intrauterine device, and must have ended previous use of hormonal preparations at least one month prior to the study.
  • Must not have a personal history of any chronic medical condition that may interfere with the aims of the study or make the experimental protocol unsafe, including but not limited to metabolic or autoimmune disease, epilepsy, endometriosis, cancer, diabetes, cardiovascular, gastrointestinal, hepatic, renal, or pulmonary disease, and no personal or first degree family history of thromboembolic events.
  • Any current cigarette smoking is exclusionary.
  • Must not report a current diagnosis of major depressive episode with peripartum onset (current episode), and must not be currently receiving treatment for premenstrual dysphoric disorder (Note: Premenstrual Dysphoric Disorder diagnosis must have been made based on prospective daily ratings).
  • Must not report any history of manic episode, any history of psychotic symptoms, or current substance use disorder.
  • Must not test positive for (unprescribed) opioid use, methamphetamine use, or cocaine use at the start of an experimental condition.

Sites / Locations

  • University of Illinois Neuropsychiatric Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Transdermal Estradiol + Placebo

Oral Micronized Progesterone + Placebo

Placebos

Arm Description

.1mg per 24 hours transdermal estradiol applied to the skin weekly, and sugar pill manufactured to mimic the progesterone pills taken twice daily by mouth, for 14 days.

100 mg oral micronized progesterone pill taken twice daily by mouth, and clear patch manufactured to mimic the E2 patch applied to the skin weekly, for 14 days.

Sugar pill designed to mimic the P4 pills taken twice daily by mouth, and clear patch manufactured to mimic the E2 patch applied to the skin weekly, for 14 days.

Outcomes

Primary Outcome Measures

Cyclical Change in Suicidal Ideation (SI) Severity
Each day, participants completed five items from the Adult Suicidal Ideation Questionnaire (ASIQ; items 1,2,9,17,19). Response options ranged from 1 (no suicidal ideation) to 6 (extreme severity of suicidal ideation). For each participant on each day, "mean daily SI" was calculated as the mean of these five items. Our outcome, Cyclical Change in SI Severity, is calculated for each person, in each condition, as the DIFFERENCE between mean daily SI during the low-risk early luteal phase days (days LH surge +1,2,3,4,5,6,7) and the high-risk perimenstrual phase days (days LH surge +11,12,13,14,15,16,17), with the subtraction carried out as Perimenstrual mean minus Early Luteal mean. Therefore, this single value represents the degree to which an individual showed perimenstrual worsening of SI within a condition.

Secondary Outcome Measures

Full Information

First Posted
April 6, 2018
Last Updated
August 18, 2022
Sponsor
University of Illinois at Chicago
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT03498313
Brief Title
Unique Effects of Perimenstrual Estradiol or Progesterone Supplementation on Perimenstrual Suicidality
Acronym
CLEAR-2
Official Title
Unique Effects of Perimenstrual Estradiol or Progesterone Supplementation on Perimenstrual Suicidality
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
July 27, 2018 (Actual)
Primary Completion Date
May 9, 2021 (Actual)
Study Completion Date
May 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Illinois at Chicago
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This within-person, crossover, 3-condition, placebo-controlled study compares the impact of three perimenstrual conditions on severity of suicidal symptoms in females with past-month suicidality but minimal risk of imminent suicide attempt. The three conditions are (1) perimenstrual withdrawal from estradiol only (during progesterone stabilization), (2) perimenstrual withdrawal from progesterone only (during estradiol stabilization), and (3) perimenstrual withdrawal from both estradiol and progesterone during placebo.
Detailed Description
Previous work from our group demonstrates that perimenstrual worsening of suicidal thoughts in females is caused by normal perimenstrual withdrawal from the ovarian steroids estradiol (E2) and progesterone (P4), since perimenstrual stabilization of E2+P4 prevented the perimenstrual worsening of suicidal ideation observed under placebo. In the present study, we follow up on that work with an additional mechanistic trial in which E2 and P4 will be stabilized in separate arms of the study. 60 (30 completers) female outpatients, with past-month suicidal ideation but minimal imminent risk for attempt, will complete self-reports and clinical interviews measuring presence and severity of suicidal ideation in each of three conditions (A, B, C: order randomized across three menstrual cycles): (A) perimenstrual E2/P4 withdrawal (under placebo), (B) perimenstrual P4 withdrawal (exogenous stabilization of E2 only), and (C) perimenstrual E2 withdrawal (exogenous stabilization of P4 only). A washout cycle will separate conditions. Analyses will compare the perimenstrual trajectories of symptoms and suicidality across the three conditions.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Suicidal Ideation
Keywords
steroid hormones, estradiol, estrogen, progesterone, depression, suicide

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
Crossover 3-condition placebo-controlled trial
Masking
ParticipantInvestigator
Masking Description
double-blind
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Transdermal Estradiol + Placebo
Arm Type
Experimental
Arm Description
.1mg per 24 hours transdermal estradiol applied to the skin weekly, and sugar pill manufactured to mimic the progesterone pills taken twice daily by mouth, for 14 days.
Arm Title
Oral Micronized Progesterone + Placebo
Arm Type
Experimental
Arm Description
100 mg oral micronized progesterone pill taken twice daily by mouth, and clear patch manufactured to mimic the E2 patch applied to the skin weekly, for 14 days.
Arm Title
Placebos
Arm Type
Placebo Comparator
Arm Description
Sugar pill designed to mimic the P4 pills taken twice daily by mouth, and clear patch manufactured to mimic the E2 patch applied to the skin weekly, for 14 days.
Intervention Type
Drug
Intervention Name(s)
Transdermal Estradiol + Placebo
Other Intervention Name(s)
Climara, sugar pill
Intervention Description
.1mg/24hr transdermal estradiol for 14 days starting day 7 after positive urine luteinizing hormone test, plus twice daily placebo pills during the same time frame.
Intervention Type
Drug
Intervention Name(s)
Oral Micronized Progesterone + Placebo
Other Intervention Name(s)
Prometrium, placebo patch
Intervention Description
100mg oral micronized progesterone twice daily for 14 days starting day 7 after positive urine luteinizing hormone test, plus weekly application of a placebo patch during the same time frame.
Intervention Type
Drug
Intervention Name(s)
Placebos
Other Intervention Name(s)
sugar pill, placebo patch
Intervention Description
Twice daily placebo pills for 14 days starting day 7 after positive urine luteinizing hormone test, plus weekly application of a placebo patch during the same time frame.
Primary Outcome Measure Information:
Title
Cyclical Change in Suicidal Ideation (SI) Severity
Description
Each day, participants completed five items from the Adult Suicidal Ideation Questionnaire (ASIQ; items 1,2,9,17,19). Response options ranged from 1 (no suicidal ideation) to 6 (extreme severity of suicidal ideation). For each participant on each day, "mean daily SI" was calculated as the mean of these five items. Our outcome, Cyclical Change in SI Severity, is calculated for each person, in each condition, as the DIFFERENCE between mean daily SI during the low-risk early luteal phase days (days LH surge +1,2,3,4,5,6,7) and the high-risk perimenstrual phase days (days LH surge +11,12,13,14,15,16,17), with the subtraction carried out as Perimenstrual mean minus Early Luteal mean. Therefore, this single value represents the degree to which an individual showed perimenstrual worsening of SI within a condition.
Time Frame
Days 1 to 17 following positive LH test

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ability to adhere to medication regimen Speaks English Assigned female at birth with intact ovaries Premenopausal Normal menstrual cycles between 25-35 days Under current care of an outpatient mental health provider with visits occurring at least once every 3 months. At least 1 year postpartum. Willing to use a barrier method of birth control during the study. Normal weight (BMI between 18.00-29.99) Must report at least some recent suicidal ideation (in the past month) at the time of recruitment. Must be categorized as having acceptably low imminent risk for suicidal crisis/attempt by a licensed clinical psychologist utilizing evidence-based clinical and research guidelines for imminent suicide risk management. Exclusion Criteria: Must not be pregnant, breastfeeding, or trying to become pregnant. Must not be taking any form of exogenous hormones or hormonal intrauterine device, and must have ended previous use of hormonal preparations at least one month prior to the study. Must not have a personal history of any chronic medical condition that may interfere with the aims of the study or make the experimental protocol unsafe, including but not limited to metabolic or autoimmune disease, epilepsy, endometriosis, cancer, diabetes, cardiovascular, gastrointestinal, hepatic, renal, or pulmonary disease, and no personal or first degree family history of thromboembolic events. Any current cigarette smoking is exclusionary. Must not report a current diagnosis of major depressive episode with peripartum onset (current episode), and must not be currently receiving treatment for premenstrual dysphoric disorder (Note: Premenstrual Dysphoric Disorder diagnosis must have been made based on prospective daily ratings). Must not report any history of manic episode, any history of psychotic symptoms, or current substance use disorder. Must not test positive for (unprescribed) opioid use, methamphetamine use, or cocaine use at the start of an experimental condition.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tory A Eisenlohr-Moul, PhD
Organizational Affiliation
University of Illinois at Chicago
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Illinois Neuropsychiatric Institute
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Unique Effects of Perimenstrual Estradiol or Progesterone Supplementation on Perimenstrual Suicidality

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