CLEAR-2: Ovarian Hormones and Suicide Risk

Sponsor

University of Illinois at Chicago (Other)

Overall Status

Completed

CT.gov ID

NCT03498313

Collaborator

National Institute of Mental Health (NIMH) (NIH)

Enrollment

Location

Arms

33.4

Actual Duration (Months)

1.8

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Suicidal Ideation	Drug: Transdermal Estradiol + Placebo Drug: Oral Micronized Progesterone + Placebo Drug: Placebos	Phase 4

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Crossover 3-condition placebo-controlled trialCrossover 3-condition placebo-controlled trial

Masking:

Double (Participant, Investigator)

Masking Description:

double-blind

Primary Purpose:

Basic Science

Official Title:

Ovarian Hormone Withdrawal and Suicide Risk: An Experimental Approach

Actual Study Start Date :

Jul 27, 2018

Actual Primary Completion Date :

May 9, 2021

Actual Study Completion Date :

May 9, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transdermal Estradiol + Placebo .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.	Drug: Transdermal Estradiol + Placebo .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. Other Names: Climara sugar pill
Experimental: Oral Micronized Progesterone + Placebo 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.	Drug: Oral Micronized Progesterone + Placebo 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. Other Names: Prometrium placebo patch
Placebo Comparator: Placebos 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.	Drug: Placebos 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. Other Names: sugar pill placebo patch

Arm

Intervention/Treatment

Experimental: Transdermal Estradiol + Placebo

.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.

Drug: Transdermal Estradiol + Placebo

.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.

Other Names:

Climara

sugar pill

Experimental: Oral Micronized Progesterone + Placebo

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.

Drug: Oral Micronized Progesterone + Placebo

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.

Other Names:

Prometrium

placebo patch

Placebo Comparator: Placebos

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.

Drug: Placebos

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.

Other Names:

sugar pill

placebo patch

Outcome Measures

Primary Outcome Measures

Mean Difference in Adult Suicidal Ideation Questionnaire [Days 11 to 17 following positive LH test, when perimenstrual symptoms typically peak]
Within-person Difference in Mean Severity of Suicidal Ideation between each of the three conditions.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts 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.