Trial Outcomes & Findings for Unique Effects of Perimenstrual Estradiol or Progesterone Supplementation on Perimenstrual Suicidality (NCT NCT03498313)

Last Updated: 2022-09-14

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

60 participants

Primary outcome timeframe

Days 1 to 17 following positive LH test

Results posted on

2022-09-14

Participant Flow

60 participants were enrolled (consented) in the study. Following a baseline phase in which participants completed daily symptom ratings and prepared to begin urinary LH testing as part of the lead-up to the first experimental period, 46 participants remained in the study and were randomized to one of six sequences of the three experimental conditions.

Participant milestones

Participant milestones
Measure	E-P-PBO Estrogen First, then Progesterone, then Placebo	E-PBO-P Estrogen, Placebo, Progesterone	P-E-PBO Progesterone, Estrogen, Placebo	P-PBO-E Progesterone, Placebo, Estrogen	PBO-E-P Placebo, Estrogen, Progesterone	PBO-P-E Placebo, Progesterone, Estrogen
Experimental Period 1 STARTED	9	8	9	5	9	6
Experimental Period 1 COMPLETED	8	7	9	4	9	6
Experimental Period 1 NOT COMPLETED	1	1	0	1	0	0
Washout Period 1 STARTED	8	7	9	4	9	6
Washout Period 1 COMPLETED	7	4	9	3	9	5
Washout Period 1 NOT COMPLETED	1	3	0	1	0	1
Experimental Period 2 STARTED	7	4	9	3	9	5
Experimental Period 2 COMPLETED	7	4	9	3	8	3
Experimental Period 2 NOT COMPLETED	0	0	0	0	1	2
Washout Period 2 STARTED	7	4	9	3	8	3
Washout Period 2 COMPLETED	3	2	9	2	6	1
Washout Period 2 NOT COMPLETED	4	2	0	1	2	2
Experimental Period 3 STARTED	3	2	9	2	6	1
Experimental Period 3 COMPLETED	3	2	9	2	6	1
Experimental Period 3 NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	E-P-PBO Estrogen First, then Progesterone, then Placebo	E-PBO-P Estrogen, Placebo, Progesterone	P-PBO-E Progesterone, Placebo, Estrogen	PBO-E-P Placebo, Estrogen, Progesterone	PBO-P-E Placebo, Progesterone, Estrogen
Experimental Period 1 Adverse Event	1	0	1	0	0
Experimental Period 1 Withdrawal by Subject	0	1	0	0	0
Washout Period 1 Anovulation	1	0	0	0	0
Washout Period 1 Withdrawal by Subject	0	3	1	0	1
Experimental Period 2 Adverse Event	0	0	0	1	2
Washout Period 2 Physician Decision	1	0	1	0	1
Washout Period 2 Withdrawal by Subject	3	2	0	2	0
Washout Period 2 Anovulation	0	0	0	0	1

Baseline Characteristics

Unique Effects of Perimenstrual Estradiol or Progesterone Supplementation on Perimenstrual Suicidality

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	E-P-PBO n=9 Participants Estrogen First, then Progesterone, then Placebo	E-PBO-P n=8 Participants Estrogen, Placebo, Progesterone	P-E-PBO n=9 Participants Progesterone, Estrogen, Placebo	P-PBO-E n=5 Participants Progesterone, Placebo, Estrogen	PBO-E-P n=9 Participants Placebo, Estrogen, Progesterone	PBO-P-E n=6 Participants Placebo, Progesterone, Estrogen	Total n=46 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants	5 Participants n=4 Participants	9 Participants n=21 Participants	6 Participants n=10 Participants	46 Participants n=115 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants	5 Participants n=4 Participants	9 Participants n=21 Participants	6 Participants n=10 Participants	46 Participants n=115 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	1 Participants n=115 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	2 Participants n=10 Participants	8 Participants n=115 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	1 Participants n=115 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants	2 Participants n=10 Participants	8 Participants n=115 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	6 Participants n=21 Participants	1 Participants n=10 Participants	27 Participants n=115 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	1 Participants n=115 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Region of Enrollment United States	9 participants n=5 Participants	8 participants n=7 Participants	9 participants n=5 Participants	5 participants n=4 Participants	9 participants n=21 Participants	6 participants n=10 Participants	46 participants n=115 Participants

PRIMARY outcome

Timeframe: Days 1 to 17 following positive LH test

Outcome measures

Outcome measures
Measure	Transdermal Estradiol + Placebo n=38 Participants .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. 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.	Oral Micronized Progesterone + Placebo n=35 Participants 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. 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.	Placebos n=35 Participants 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. 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.
Cyclical Change in Suicidal Ideation (SI) Severity	-.22 units on a scale Standard Error .05	-.05 units on a scale Standard Error .07	.25 units on a scale Standard Error .11

Adverse Events

Transdermal Estradiol + Placebo

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Oral Micronized Progesterone + Placebo

Serious events: 2 serious events

Other events: 10 other events

Deaths: 0 deaths

Placebos

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Transdermal Estradiol + Placebo n=38 participants at risk .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. 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.	Oral Micronized Progesterone + Placebo n=35 participants at risk 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. 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.	Placebos n=35 participants at risk 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. 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.
Respiratory, thoracic and mediastinal disorders Hospitalization for Respiratory Infection	0.00% 0/38 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	2.9% 1/35 • Number of events 1 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
Psychiatric disorders Hospitalization for Worsening Suicidal Ideation	0.00% 0/38 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	2.9% 1/35 • Number of events 1 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.

Other adverse events

Other adverse events
Measure	Transdermal Estradiol + Placebo n=38 participants at risk .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. 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.	Oral Micronized Progesterone + Placebo n=35 participants at risk 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. 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.	Placebos n=35 participants at risk 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. 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.
General disorders Headache	10.5% 4/38 • Number of events 4 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	14.3% 5/35 • Number of events 5 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	17.1% 6/35 • Number of events 6 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
Reproductive system and breast disorders Breast Discomfort	10.5% 4/38 • Number of events 4 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	2.9% 1/35 • Number of events 1 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	11.4% 4/35 • Number of events 4 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
Musculoskeletal and connective tissue disorders Muscle Pain	0.00% 0/38 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	5.7% 2/35 • Number of events 2 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
General disorders Nausea	5.3% 2/38 • Number of events 2 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	5.7% 2/35 • Number of events 2 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	8.6% 3/35 • Number of events 3 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
Skin and subcutaneous tissue disorders Skin Irritation	7.9% 3/38 • Number of events 3 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
General disorders Dizziness	2.6% 1/38 • Number of events 1 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
Eye disorders Vision Changes	2.6% 1/38 • Number of events 1 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.
Psychiatric disorders Self-Report of Adverse Mood Changes	0.00% 0/38 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	5.7% 2/35 • Number of events 2 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.	0.00% 0/35 • Three different two-week conditions, each with at least one month washout between (i.e., 6 weeks total). Adverse events were assessed via phone daily during the six weeks of medication use.

Additional Information

Dr. Tory Eisenlohr-Moul, Assistant Professor of Psychiatry

University of Illinois at Chicago

Phone: 859-317-0503

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place