Conditions: Suicidal Ideation
Keywords: Steroid hormones Estradiol Progesterone Depression Suicide
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 30
Healthy volunteers: no

Brief summary:
This within-person, crossover, 2-condition, placebo-controlled study compares the impact of two perimenstrual conditions on severity of suicidal symptoms in females with past-month suicidality but minimal risk of imminent suicide attempt. The two conditions are (1) natural perimenstrual withdrawal from estradiol and progesterone (during placebo), (2) perimenstrual stabilization of estradiol and progesterone using transdermal estradiol and oral micronized progesterone.

Detailed description:
A large number of observational studies have documented increased risk of suicide attempt, suicide death, and more lethal attempts during the perimenstrual (around menses) window of the female reproductive cycle; however, no experiments have investigated the causal role of ovarian steroid changes across the natural perimenstrual period in risk factors for acute suicidality. In response, the proposed experimental work investigates a causal role of perimenstrual withdrawal from the hormones estradiol (E2) and progesterone (P4) in previously-documented acute perimenstrual increases in suicidality.

Participants are 30 women between the ages of 18 and 45 with current suicidal ideation but minimal risk for suicide attempt. Using a placebo-controlled, crossover within-person design, the experiment tests the hypothesis that suicidality will be heightened during natural perimenstrual E2/P4 withdrawal (under placebo), but that experimental prevention of this perimenstrual E2/P4 withdrawal (with exogenous administration of E2/P4 hormones) will prevent these perimenstrual increases in suicidality and associated risk factors.

Arms:
arm 1: Beginning 7 days after ovulation, active treatment begins 7 days after ovulation with an estradiol transdermal patch (0.1 mg/24 hrs) applied to the skin weekly (spanning 14 days of treatment) along with (active) 100 mg oral micronized progesterone capsules taken twice daily by mouth for 14 days. A 1-month washout is observed. Then, beginning 7 days after ovulation, inactive placebo capsules will be taken twice daily by mouth along with the application of inactive clear patches applied to the skin weekly for 14 days. arm 2: Beginning 7 days after ovulation, inactive placebo capsules will be taken twice daily by mouth along with the application of inactive clear patches applied to the skin weekly for 14 days. After completing a 1-month washout, active treatment begins 7 days after ovulation with an (active) estradiol transdermal patch applied to the skin weekly (spanning 14 days of treatment) along with (active) 100 mg oral micronized progesterone capsules taken twice daily by mouth for 14 days.

Interventions: intervention 1: Estradiol Transdermal Patch 0.1 mg/24 hrs intervention 2: Oral Micronized Progesterone intervention 3: Inactive Clear Patch intervention 4: Placebo capsule
Intervention descriptions: intervention 1: Estradiol transdermal patch delivering 0.1 mg/24 hour administered by affixing to skin for 14 days starting on day 7 after ovulation intervention 2: 100 mg oral micronized progesterone taken orally twice daily for 14 days starting day 7 after ovulation intervention 3: Matching placebo patch administered by affixing to skin for 14 days starting on day 7 after ovulation intervention 4: Matching placebo capsules administered twice daily for 14 days starting day 7 after ovulation

Protocol document:
Prot_SAP_000.pdf: 
 
Effect of Perimenstrual Ovarian Steroid 
Supplementation on Perimenstrual 
Suicidality  
 
(NIMH Grant Name: “Ovarian Hormone Withdrawal and Suicide 
Risk: An Experimental Approach”; K99MH109667; UNC IRB 
number 16-2078) 
 
 
 
NCT number  
Document Date 10-02-16 
 
 
 
03720847


ii 
 
Effect of Perimenstrual Ovarian Steroid 
Supplementation on Perimenstrual Suicidality  
(NIH Grant Name: Ovarian Hormone Withdrawal and Suicide 
Risk: An Experimental Approach) 
 
Protocol Identifying Number: IRB # 16-2078 
Principal Investigator: Tory Eisenlohr-Moul, Ph.D. 
IND/IDE Sponsor: Not applicable 
Funded by: NIMH (K99MH109667) 
Date: 2 October 2016 
 


ii 
 
Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................. i 
STATEMENT OF COMPLIANCE ..................................................................................... i 
PROTOCOL SUMMARY .................................................................................................. i 
SCHEMATIC OF STUDY DESIGN .................................................................................iv 
1 
KEY ROLES .......................................................................................................... 6 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE .................................................................................................................... 7 
2.1 
Background Information ................................................................................. 7 
2.2 
Rationale ........................................................................................................ 7 
2.3 
Potential Risks and Benefits ........................................................................ 10 
2.3.1 
Known Potential Risks .................................................................. 10 
2.3.2 
Known Potential Benefits .............................................................. 12 
3 
OBJECTIVES AND PURPOSE ........................................................................... 12 
4 
STUDY DESIGN AND ENDPOINTS .................................................................... 12 
4.1 
Description of the Study Design ................................................................... 12 
4.2.1 
Primary Endpoint ........................................................................... 15 
4.2.2 
Secondary Endpoints .................................................................... 15 
4.2.3 
Exploratory Endpoints ................................................................... 15 
5 
STUDY ENROLLMENT AND WITHDRAWAL ..................................................... 15 
5.1 
Participant Inclusion Criteria ........................................................................ 15 
5.2 
Participant Exclusion Criteria ....................................................................... 23 
5.3 
Strategies for Recruitment and Retention .................................................... 24 
5.4 
Participant Withdrawal or termination .......................................................... 26 
5.4.1 
Reasons for Withdrawal or Termination ........................................ 26 
5.4.2 
Handling of Participant Withdrawals or termination ....................... 27 
5.5 
Premature Termination or Suspension of Study .......................................... 27 
6 
STUDY AGENT ................................................................................................... 28 
6.1 
Study Agent(s) and Control Description ....................................................... 28 
6.1.1 
Acquisition ..................................................................................... 28 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ..................... 28 
6.1.3 
Product Storage and Stability ........................................................ 28 
6.1.4 
Preparation ................................................................................... 28 
6.1.5 
Dosing and Administration ............................................................ 28 
6.1.6 
Route of Administration ................................................................. 28 
6.1.7 
Starting Dose and Dose Escalation Schedule ............................... 28 
6.1.8 
Dose Adjustments/Modifications/Delays ....................................... 29 
6.1.9 
Duration of Therapy ...................................................................... 29 
6.1.10 
Tracking of Dose ........................................................................... 29 
6.1.11 
Device Specific Considerations ..................................................... 29 
6.2 
Study agent Accountability Procedures ....................................................... 29 
7 
STUDY PROCEDURES AND SCHEDULE ......................................................... 29 
7.1 
Study Procedures/Evaluations ..................................................................... 29 
7.1.1 
Study specific procedures ............................................................. 29 
7.1.2 
Standard of care study procedures ............................................... 31 
7.2 
Laboratory Procedures/Evaluations ............................................................. 31 


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7.2.1 
Clinical Laboratory Evaluations ..................................................... 31 
7.2.2 
Other Assays or Procedures ........... Error! Bookmark not defined. 
7.2.3 
Specimen Preparation, Handling, and Storage ............................. 31 
7.2.4 
Specimen Shipment ...................................................................... 32 
7.3 
Study Schedule ............................................................................................ 32 
7.3.1 
Screening ...................................................................................... 32 
7.3.2 
Enrollment/Baseline ...................................................................... 32 
7.3.3 
Follow-up ...................................................................................... 32 
7.3.4 
Final Study Visit ............................................................................ 34 
7.3.5 
Early Termination Visit .................................................................. 34 
7.3.7 
Schedule of Events Table ............................................................. 34 
7.4 
Justification for Sensitive Procedures .......................................................... 35 
7.5 
Concomitant Medications, Treatments, and Procedures ............................. 36 
7.5.1 
Precautionary Medications, Treatments, and Procedures ............. 36 
7.6 
Prohibited Medications, Treatments, and Procedures ................................. 36 
7.7 
Prophylactic Medications, Treatments, and Procedures .............................. 36 
7.8 
Rescue Medications, Treatments, and Procedures ..................................... 36 
7.9 
Participant Access to Study Agent At Study Closure ................................... 36 
8 
ASSESSMENT OF SAFETY ............................................................................... 36 
8.1 
Specification of Safety Parameters .............................................................. 37 
8.1.1 
Definition of Adverse Events (AE) ................................................. 37 
8.1.2 
Definition of Serious Adverse Events (SAE) ................................. 37 
8.1.3 
Definition of Unanticipated Problems (UP) .................................... 37 
8.2 
Classification of an Adverse Event .............................................................. 38 
8.2.1 
Severity of Event ........................................................................... 38 
8.2.2 
Relationship to Study Agent .......................................................... 38 
8.2.3 
Expectedness................................................................................ 39 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up ............. 39 
8.4 
Reporting Procedures .................................................................................. 40 
8.4.1 
Adverse Event Reporting .............................................................. 40 
8.4.2 
Serious Adverse Event Reporting ................................................. 40 
8.4.3 
Unanticipated Problem Reporting ................................................. 41 
8.4.4 
Events of Special Interest ............................................................. 41 
8.4.5 
Reporting of Pregnancy ................................................................ 41 
8.5 
Study Halting Rules ..................................................................................... 41 
8.6 
Safety Oversight .......................................................................................... 42 
9 
CLINICAL MONITORING..................................................................................... 42 
10 
STATISTICAL CONSIDERATIONS ..................................................................... 43 
10.1 
Statistical and Analytical Plans .................................................................... 43 
10.2 
Statistical Hypotheses.................................................................................. 43 
10.3 
Analysis Datasets ........................................................................................ 43 
10.4 
Description of Statistical Methods ................................................................ 43 
10.4.1 
General Approach ......................................................................... 43 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ................................. 44 
10.4.3 
Analysis of the Secondary Endpoint(s) ......................................... 44 
10.4.4 
Safety Analyses ............................................................................ 44 


iv 
 
10.4.5 
Adherence and Retention Analyses .............................................. 46 
10.4.6  
Baseline Descriptive Statistics ...................................................... 46 
10.4.7 
Planned Interim Analyses ............................................................. 46 
10.4.9 
Multiple Comparison/Multiplicity .................................................... 47 
10.4.10 
Tabulation of Individual Response Data ........................................ 47 
10.4.11 
Exploratory Analyses .................................................................... 47 
10.5 
Sample Size ................................................................................................. 47 
10.6 
Measures to Minimize Bias .......................................................................... 48 
10.6.1 
Enrollment/ Randomization/ Masking Procedures......................... 48 
10.6.2 
Evaluation of Success of Blinding ................................................. 48 
10.6.3 
Breaking the Study Blind/Participant Code ................................... 48 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .... 48 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................... 48 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS................................................ 49 
13.1 
Ethical Standard .......................................................................................... 49 
13.2 
Institutional Review Board ........................................................................... 49 
13.3 
Informed Consent Process .......................................................................... 49 
13.3.1 
Consent/assent and Other Informational Documents Provided to 
Participants 
49 
13.3.2 
Consent Procedures and Documentation ..................................... 49 
13.4 
Participant and data Confidentiality ............................................................. 50 
13.4.1 
Research Use of Stored Human Samples,Specimens or Data ..... 50 
13.5 
Future Use of Stored Specimens ................................................................. 51 
14 
DATA HANDLING AND RECORD KEEPING ...................................................... 51 
14.1 
Data Collection and Management Responsibilities ...................................... 51 
14.2 
Study Records Retention ............................................................................. 52 
14.3 
Protocol Deviations ...................................................................................... 52 
14.4 
Publication and Data Sharing Policy ............................................................ 52 
15 
STUDY ADMINISTRATION ................................................................................. 53 
15.1 
Study Leadership ......................................................................................... 53 
16 
CONFLICT OF INTEREST POLICY .................................................................... 53 
17  
LITERATURE REFERENCES ............................................................................. 53 
APPENDIX .................................................................................................................... 70 
 


 
 
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LIST OF ABBREVIATIONS 
 
E2 
17-beta-estradiol 
P4 
progesterone 
RCT 
Randomized controlled trial 
SITBI 
Self-Injurious Thoughts and Behaviors Interview 
UWRAP/LRAP University of Washington Risk Assessment and Management 
Protocol/Linehan Risk Assessment and Management Protocol 
EXP 
Experimental 
PL 
Placebo 
EMA 
Ecological Momentary Assessment 
CESD 
Center for Epidemiologic Studies Depression Scale 
BHI 
Beck Hopelessness Inventory 
STAI 
State-Trait Anxiety Inventory 
UPPS-P 
An Impulsivity Scale measuring Urgency, lack of Premeditation, lack of 
Perseverance, Sensation seeking, and Positive Urgency. 
SSES 
State Self-Esteem Scale 
FT-IRAP 
Future-Thinking Implicit Relational Assessment Procedure (Hopelessness 
Task) 
SAR-IAT 
Social Acceptance and Rejection Implicit Association Test (Negative Social 
Appraisals Task) 
SST 
Stop-Signal Task (Inhibitory Control Task) 
DPT 
Dot Probe Task (Threat Sensitivity Task) 
SCID 
Structured Clinical Interview for Diagnosis 
IDS 
Investigational Drug Services 
 
STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on 
the Protection of Human Subjects (45 CFR Part 46), and the NIMH Terms of Award. The 
Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the sponsor and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection Training.  
 
PROTOCOL SUMMARY 
Title: 
Ovarian Hormone Withdrawal and Suicide Risk: An Experimental 
Approach 
Précis: 
45 female outpatients with suicidal ideation but minimal1,2 imminent 
risk for attempt will complete behavioral tasks measuring 
hopelessness, social appraisals, inhibitory control, and threat 
sensitivity as well as clinical interviews measuring suicidality in each 
of two conditions (order randomized across two menstrual cycle 
phases): (1) natural perimenstrual E2/P4 withdrawal (placebo), 
and (2) exogenous stabilization of physiologic premenstrual 
(luteal phase) E2/P4 to prevent withdrawal. Analyses will compare 


 
 
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symptoms and suicidality under placebo to symptoms and suicidality 
under exogenous stabilization of E2 and P4.  
Objectives: 
 
The central aim of this mechanistic study is to experimentally 
test a pathophysiologic mediational model in which E2/P4 
withdrawal increases perimenstrual suicidal desire (via increased 
hopelessness and negative social appraisals) and suicidal action 
capacity (via reduced inhibitory control and increased threat 
sensitivity). We predict that natural perimenstrual E2/P4 withdrawal 
(compared to stabilization) will be associated with greater 
perimenstrual suicidal desire (partially mediated by task performance 
indicating increased hopelessness and negative social appraisals) 
and action capacity (partially mediated by task performance indicating 
decreased inhibitory control and increased threat sensitivity). 
 
 
 
 
Endpoint 
Primary:  
 
(1) Mean Within-Person Condition Difference (7 final placebo 
days – 7 final stabilization days) of SITB Suicidal Ideation 
subscale score (operationalization of suicidal desire) 
 
(2) Mean Within-Person Condition Difference (7 final placebo 
days – 7 final stabilization days) of SITB Suicidal Planning 
subscale score (operationalization of suicidal action capacity) 
 
Secondary: 
 
(1) Mean Within-Person Condition Difference (7 final placebo 
days – 7 final stabilization days) of BHI Hopelessness Score  
 
(2) Mean Within-Person Condition Difference (7 final placebo 
days – 7 final stabilization days) of CES-D Depression Total 
Score  
 
(3) Mean Within-Person Condition Difference (7 final placebo 
days – 7 final stabilization days) of UPPS-P Lack of 
Premeditation Impulsivity subscale 
 
(4) Mean Within-Person Condition Difference (7 final placebo 
days – 7 final stabilization days) of PROMIS Anxiety Total 
Score 
 
(5) Mean Within-Person Condition Difference (7 final placebo 
days – 7 final stabilization days) of SSES Social Evaluation/ 
Rejection Sensitivity subscale 
 
Population: 
45 female outpatients with suicidal ideation but minimal1,2 imminent 
risk for attempt 
Phase: 
N/A – Mechanistic Experiment 


 
 
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Number of Sites 
enrolling 
participants: 
1 
Description of Study 
Agent : 
Transdermal Estradiol .1mg/24hr weekly for two weeks, and Oral 
Micronized Progesterone 200mg (100mg each morning, 100mg 
each evening) for two weeks 
Study Duration: 
20 months 
Participant Duration: 
~3 menstrual cycles (1 menstrual cycle lasts, on average, ~28 days). 
Therefore, average participation will last roughly 3.5 months. 
 
 
 


 
 
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SCHEMATIC OF STUDY DESIGN 
 
Screening and  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visits 1-3 
 
 
 
 
 
 
Visits 4-6 
 
 
 
 
Perform initial telephone screen of potential subjects by inclusion and exclusion criteria, schedule enrollments as 
appropriate. At Enrollment, obtain informed consent if eligible and interested. Administer SCID, SITBI.Train 
participants in ovulation testing. 
Days 7, 14, and 22 Following 1st positive Ovulation test:  
Administer Condition 1 Intervention (Placebo or Experimental).  
Complete Interview Assessment of suicidiality (SITBI). 
Complete Computerized Tasks Measuring Inhibitory Control, Hopelessness, Rejection 
Sensitivity, and  Threat Sensitivity. Assess side effects.  
Final Visit to Evaluate Suicide Risk 
and Facilitate Appropriate 
Referrals as Needed  
Randomized Subject to a Condition Order 
Condition Order 2: Experimental during visits 1-3,  
Placebo during visits 4-6 (n=15) 
Condition Order 1: Placebo during visits 1-3,  
Experimental during visits 4-6 (n=15) 
Days 7, 14, and 22 Following 2nd positive Ovulation test:  
Administer Condition 2 Intervention (Placebo or Experimental).  
Complete Interview Assessment of suicidiality (SITBI). 
Complete Computerized Tasks Measuring Inhibitory Control, Hopelessness, Rejection 
Sensitivity, and  Threat Sensitivity. Assess side effects.  


 
 
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Design Figure. Overview of the Two Within-Person Crossover Study Conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1 
KEY ROLES 
 
Mark Chavez, Ph.D. – NIMH Program Officer, Email: mchavez1@mail.nih.gov; Phone: (301) 443-8942 
 
Tory Eisenlohr-Moul, Ph.D. – Primary Investigator, Clinical Psychologist, Clinician Responsible for Suicide 
Risk Assessment and Management; University of North Carolina at Chapel Hill, 2218 Nelson Highway, Suite 3, 
Chapel Hill, NC 27517. Email: t.eisenlohr.moul@gmail.com; moul@med.unc.edu.  Phone: 859-317-0503.  
 
Susan Girdler, Ph.D. – Primary Mentor to the PI, Experimental Psychologist; University of North Carolina at 
Chapel Hill; 2218 Nelson Highway, Suite 3, Chapel Hill, NC 27517. Email: s_girdler@med.unc.edu.  Phone: 
919-966-2179.  
 
Mitch Prinstein, Ph.D. – Supervising Clinical Psychologist Regarding Suicide Risk Assessment; 
University of North Carolina at Chapel Hill, 240 Davie Hall, Chapel Hill, NC 27517. Email: 
mitch.prinstein@unc.edu.  Phone: 919-962-3988.  
 
David Rubinow, M.D. (Primary Medical Expert) – Medical Monitor, Supervising Physician Psychiatrist 
Regarding Hormone Administration; University of North Carolina at Chapel Hill, Campus Box 7160, Chapel 
Hill, NC 27599. Email: david_rubinow@med.unc.edu. 
 
Steve Young, M.D./Ph.D. – Consulting Physician Gynecologist, Consultant to Dr. Rubinow; University of 
North Carolina at Chapel Hill, Chapel Hill, NC 27599. Email: steven_young@med.unc.edu. Phone: (919) 966-
5288.  
 
Joe Hodges, Medical Technician – University of North Carolina at Chapel Hill, 2218 Nelson Highway, Suite 
3, Chapel Hill, NC 27517. Email: joe_hodges@med.unc.edu. Phone: (919) 972-7496.  
 
Katherine McCann, Project Manager – University of North Carolina at Chapel Hill, 2218 Nelson Highway, 
Suite 3, Chapel Hill, NC 27517. Email: katherine_mccann@med.unc.edu. Phone: (919) 972-7496.  
 
Cheryl Walker, Endocrine Assay Lab Director – University of North Carolina at Chapel Hill, Department of 
Psychiatry Endocrine Assay Lab Director, Chapel Hill, NC, 27599. Email: Cheryl_walker@med.unc.edu. 
Phone: (919) 632-1427.  
 
Kai Xia, Ph.D., Study Biostatistician – University of North Carolina at Chapel Hill, Department of 
Biostatistics, Chapel Hill, NC, 27599. Email: kxia@email.unc.edu. Phone: (919) 843-5508. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
 
Suicide is the second leading cause of death among women of reproductive age, yet we cannot reliably 
predict when a woman will attempt suicide. Suicide accounts for 13% of all deaths among reproductive-age 
American females69. Although existing models of suicide risk provide information about long-term, stable risk 
stemming from factors such as depression, interpersonal sensitivity, anxiety, or impulsivity, little is known about 
when these or other factors will translate into acute risk for a suicide attempt5,6,70. By directly studying 
suicidal individuals3 and focusing on biologic triggers and cognitive/behavioral mediators of acute changes in 
suicide risk, the present research responds to public calls from the U.S. President, Congress, Surgeon General, 
and the NIMH-co-sponsored Suicide Research Prioritization Agenda5, to identify strong predictors of acute 
suicide risk6. Such work is imperative in developing targeted interventions for stabilizing and reducing suicidality, 
and will improve the precision and effectiveness of critical efforts to block suicide attempts.  
 
Perimenstrual (around menses) withdrawal from estradiol (E2) and progesterone (P4) may represent a 
time-varying biological mechanism of acute suicide risk. The perimenstrual period, which is characterized 
by withdrawal from E2 and P4, is associated with more hospitalization for suicide attempts54-56,71, more lethal 
attempts55, and suicide deaths57. Despite these associations, no research has examined a causal role of 
perimenstrual ovarian steroid withdrawal in suicidality. The rationale for studying hormone withdrawal as a 
predictor of suicidality comes from work showing that withdrawal from normal levels of E2/P4, rather than differing 
absolute levels, precipitates affective symptoms and impulsivity in susceptible individuals39,72.  
 
The experiment will test a model in which perimenstrual E2/P4 withdrawal (vs. experimental luteal 
stabilization via transdermal E2 and oral micronized P4; STUDY AGENT) increases acute risk for 
suicidality by negatively modulating mediating cognitive behavioral constructs (hopelessness, social appraisals, 
inhibitory control, threat sensitivity) and parallel clinical symptoms (depression, impulsivity, rejection sensitivity, 
anxiety). To maximize both safety and generalizability, we will study women with suicidal ideation but minimal1,2 
imminent risk for suicide attempt. 
 
Theoretical Underpinning for Mediating Constructs. Selection of mediating constructs through which ovarian 
steroid withdrawal is most likely73,74 to influence suicide risk is informed by the Interpersonal Theory of 
Suicide61,75, which posits that suicidal behavior arises from two acute risk factors: Suicidal Desire—a wish to 
die, and Suicidal Action Capacity—a readiness to act on urges. Suicidal desire is strongly predicted by 
hopelessness and negative social appraisals (thwarted belongingness, perceived burdensomeness)61,76. 
Suicidal action capacity is predicted by poor inhibitory control77 and threat sensitivity—a tendency toward 
detection and reactions to threats (fostered by extreme stress exposure)63,77. Because this is an integrative 
theory, the constructs measured here will allow testing of a variety of theories (e.g., Neurocognitive Theory60).  
 
Ovarian Steroid Changes Robustly Modulate Key Mediators of Suicidal Desire and Action Capacity 
 
1. Hopelessness repeatedly emerges as the most robust prospective predictor of suicidal desire in 
inpatients78 and outpatients59. Furthermore, hopelessness58 and suicide60,62,79 share functional alterations of 
the dorsomedial prefrontal cortex, supporting a central role of hopelessness in suicidality. 
Ovarian steroid withdrawal may increase hopelessness (and associated symptoms of depression). In 
animals, ovarian steroid withdrawal increases depressive behavior via GABAergic75 and serotonergic76,77 
mechanisms, whereas E2 specifically is known to exert antidepressant effects.78  
2. Negative social appraisals predict suicidal desire. Relationships are central to our ability to survive and 
thrive80. Perceptions of social rejection are experienced as painful81,82 and increase suicidal desire61—
particularly in reproductive-age women83,84. Additionally, suicidality is associated with altered function of brain 
regions associated with experiences of social exclusion and rejection60.  
Ovarian steroid withdrawal may increase negative social appraisals (and associated symptoms of rejection 
sensitivity). In animals, E2 and P4 facilitate social motivation and behavior85-87, and ovarian steroid withdrawal 
precipitates social withdrawal67. In women, elevated luteal P4 correlates with social motivation88  and attention 


 
 
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to social-affiliative opportunities89. The PI’s longitudinal work indicates that ovarian steroid withdrawal predicts 
increased daily appraisals of social rejection in women at elevated suicide risk8,40.  
3. Poor inhibitory control enables suicidal desire to escalate into suicidal action63,90. Suicidal ideation alone 
is a poor predictor of suicidal behavior6; however, the addition of poor inhibitory control robustly predicts 
suicide attempts, suggesting its relevance for suicidal action capacity64,91,92. Suicide attempters and victims 
show deficiencies in the functioning of inhibitory circuits63,93-97.  
Ovarian steroid withdrawal may reduce inhibitory control (and increase associated symptoms of 
impulsivity). Cyclical E2/P4 withdrawal predicts poorer inhibitory control, greater impulsivity,8,98-100  and 
decreased frontal cortex inhibitory activity101, while high, stable ovarian steroids increase frontal cortex inhibitory 
activation102,103. Cyclical reductions in inhibition are particularly marked in women with low prefrontal dopamine, 
which corresponds to the greater impulsivity found in suicide victims60,104. In animals, baseline impulsive behavior 
is a risk factor for greater sensitivity to ovarian steroid withdrawal105,106.  
4. Threat sensitivity, (defined as increased attention and reflexive responses to threats), predicts suicidal 
behavior63,84,107. Repeated engagement of physiological stress systems also leads to HPA axis 
dysregulation, which prospectively predicts suicide attempts among chronically suicidal individuals108. Other 
research in suicide victims indicate that generalized threat sensitivity and reactivity to stimuli in daily life are 
acutely elevated prior to fatal suicidal behavior107. 
Ovarian steroid withdrawal may increase threat sensitivity (and associated symptoms of anxiety). In 
animals, E2/P4 withdrawal increases threat sensitivity and reactivity65 and causes threat-sensitizing alterations 
in associated brain circuitry, including the amygdala109-111, the bed nucleus of the stria terminalis111,112, and the 
periaqueductal grey113,114, mediated by increased expression of GABAA receptor subunits that elicit anxiogenic 
effects of P4-derived neurosteroids109,115-121. In women, correlates of suicidality including social stress122, social 
isolation123, lifetime abuse40, impulsivity105, and PTSD 124,125, predict greater effects of ovarian steroid withdrawal 
on threat sensitivity. Cyclical reductions in E2/P4 correlate with morphological and functional changes in CNS 
fear and anxiety circuitry, especially amygdala sensitivity73,126,127.  
 
Despite robust animal and correlational human evidence that E2/P4 withdrawal negatively modulates key 
mediators of suicide risk as outlined above, the present research will be the first to experimentally confirm 
(or refute) a pathophysiologic role for steroid hormone withdrawal on suicide risk factors in humans, 
generally, and in at risk women, specifically. The study delineates the within-person effects of ovarian steroid 
withdrawal on suicidal desire (via mediators hopelessness and social appraisals), and suicidal action capacity 
(via mediators inhibitory control and threat sensitivity). 
 
 
 
2.2 
RATIONALE  
 
The 
objective 
of 
this 
experiment 
is 
to 
experimentally determine the pathophysiological 
role of perimenstrual ovarian steroid hormone 
withdrawal on acute suicide risk.   Suicidal 
behavior arises from two proximal risk factors: 
Suicidal desire, defined as the wish to die, and 
suicidal action capacity, defined as a readiness to 
act on suicidal urges. Hopelessness58-60  and 
Negative social appraisals60-62 are constructs 
reflecting dysregulation in central reward and social 
processing networks, and, in turn, strongly predict 
suicidal desire.  Poor inhibitory control60,63 and 
threat sensitivity60,63,64 (cognitive bias to interpret 
stimuli in a threat-related manner) are constructs 
reflecting dysregulation in central cognitive control 
and threat avoidance networks, and, in turn, are 
strong predictors of suicidal action capacity (right 
side of Figure at right).  


 
 
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The RATIONALE for examining ovarian steroid withdrawal in suicide risk stems from evidence that 
withdrawal from estradiol (E2) and progesterone (P4), such as that occurring naturally during the perimenstrual 
timeframe,  modulate each of the mediating constructs and associated clinical symptoms8 (Figure above) toward 
risk, exerting robust anxiogenic, depressogenic, and impulsogenic effects in animals65-67 and increasing 
depression, anxiety, rejection sensitivity, and impulsivity in susceptible women (preliminary work by PI)8,40. 
However, no experimental work has directly evaluated whether perimenstrual E2/P4 withdrawal 
influences suicidality. The experiment will determine the effects of perimenstrual E2/P4 withdrawal on suicidal 
desire and action capacity in at-risk women, testing mediation by risk-related behavioral constructs.  
 
Design Overview: 30 female outpatients with suicidal ideation but minimal1,2 imminent risk for attempt will 
complete behavioral tasks measuring hopelessness, social appraisals, inhibitory control, and threat sensitivity 
as well as clinical interviews in each of two conditions (order randomized across two menstrual cycle phases): 
(1) natural perimenstrual E2/P4 withdrawal (placebo), and (2) exogenous stabilization of physiologic 
premenstrual (luteal phase) E2/P4 to prevent withdrawal. Daily calls will also assess symptoms and 
suicidality.  
 
 
CENTRAL HYPOTHESIS: Experimentally test a pathophysiologic mediational model in which late luteal 
(perimenstrual) E2/P4 withdrawal (vs. experimental luteal E2/P4 stabilization) increases suicidal desire (via 
increased hopelessness and negative social appraisals) and suicidal action capacity (via reduced inhibitory 
control and increased threat sensitivity). We predict that natural E2/P4 withdrawal (compared to stabilization) will 
increase reports of suicidal desire (partially mediated by task performance indicating increased hopelessness 
and negative social appraisals) and action capacity (partially mediated by task performance indicating decreased 
inhibitory control and increased threat sensitivity). 
 
JUSTIFICATION OF E2/P4 DOSING AND SCHEDULE 
 
In collaboration with Drs. Girdler, Young, and Rubinow, the PI has chosen formulations that are bioidentical to 
human E2 and P4 and will mimic luteal phase concentrations or E2 and P4. 
 
General Rationale for Route and Dose of E2 and P4. We will use Climara® 7 day transdermal E2 patches. 
Peak levels of E2 with Climara (~45 pg/mL), achieved within 24 hrs., correspond roughly to normative luteal E2 
levels4. No transdermal P4 is available. Although transdermal synthetic progestins are available, these molecules 
have a high affinity for androgen and mineralocorticoid receptors, limiting their usefulness for testing our 
hypotheses. Thus, oral prometrium will be dosed b.i.d. to achieve luteal P4 levels4 to create more steady-state 
levels and minimize the variability that can occur with the oral route.  
 
Rationale for Timing and Duration of E2/P4. Administration for 14 days, starting 7 days after a positive urine 
test for ovulation, will span the range of time in which natural perimenstrual withdrawal would occur and prevent 
natural withdrawal, thereby allowing us to determine the effects of natural hormone withdrawal vs. experimentally 
stabilized hormones across the same perimenstrual time period of the menstrual cycle.  
 
Compliance checks: Participants will: 1) be educated on the importance of replacing their patches every 7 
days, with individualized strategies to enhance compliance; 2) be asked about patch adherence and pill 
compliance on each daily call; 3) record date of patch application on calendars, reviewed at lab visits; 4) bring 
used and unused patches to visits; 5) be given extra patches for immediate replacement; and 6) Serum Levels 
of E2 and P4 will be collected at each session to both confirm compliance and that exogenous hormones 
replicate physiologic4 luteal phase levels.  
 
Specific Rational for Route and Dose of Estradiol (E2). By avoiding the first-pass metabolic effects of oral 
estrogen, transdermal E2 creates more stable blood levels and a more physiologic profile of E2 relative to its 
metabolites estrone and estriol169-171. Transdermal E2 also has a superior safety profile than oral estrogen for 
thromboembolic and metabolic risk172-174. The use of a 7 day transdermal system provides significantly more 


 
 
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stable concentrations and fewer patch adherence problems than twice weekly patches175. Climara® 7 day 
patches will be employed because the adhesive layer of the matrix patch (vs. reservoir systems) consists of 
polymeric acrylate or vinyl acetate in which the E2 molecules are distributed to continuously releases E2, which 
is transported across the skin leading to sustained circulating levels of E2 during each 7-day period. Levels of 
E2 achieved in pharmacological studies with Climara patches at the .1mg/24hrs dosage correspond roughly to 
normative luteal levels of E24. Climara achieves peak levels of E2 within 24 hours.  
 
Specific Rationale for Route and Dose of Progesterone (P4). No transdermal P4 is available. Although 
transdermal synthetic progestins are available, these molecules have a high affinity not only for the progesterone 
receptor but also for the androgen and mineralocorticoid receptors, limiting their usefulness for testing our 
hypotheses. Therefore, 200mg oral prometrium will be dosed daily (100mg each morning, 100mg each 
evening) to achieve luteal levels P44 to create more steady-state levels and minimize the greater variability 
(peaks and troughs) that can occur with the oral route. Prometrium peaks within 3 hours and declines throughout 
the next 24 hours.  
 
Other possible hormone manipulations were considered: a) mid-luteal administration of human chorionic 
gonadotropin to extend the luteal phase by preserving the corpus luteum, which would not isolate E2/P4 
withdrawal from other hormones; b) mid-luteal GNRH antagonist administration to precipitously drop hormones, 
which would have a menopausal side effect profile and a precipitous decline in E2/P4 that would not resemble 
perimenstrual E2/P4 decline; c) use of continuous oral contraceptives to eliminate cyclical hormone flux, which 
would stabilize E2/P4 in follicular phase ranges and not allow modeling of luteal phase levels.  
 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
 
1) Psychological Symptom Assessment 
 
Clinical interviews and self-report assessments contain questions regarding sensitive personal information, 
including severe psychological symptoms such as suicidal and other impulsive behaviors (e.g., substance 
abuse). As a result, participants may become upset or embarrassed when discussing current or past 
distressing life events and behaviors. On the other hand, recent evidence suggests that research questions 
pertaining to potentially distressing topics such as psychiatric symptoms, suicidality, and sexual or physical 
abuse do not significantly increase distress or acute suicide risk in women who report these issues3,164. The 
chance of increased distress is necessary in order to assess how symptoms change in response to 
perimenstrual hormone withdrawal (vs. stabilization). 
 
2) Effects of the Ovarian Hormone Stabilization Protocol on Mood/Anxiety and Behavior 
 
Mood/Anxiety. As the population being studied in this protocol will have elevated psychiatric symptoms, and 
as ovarian hormone changes are implicated in depressive symptoms in some women39,50, it is possible that 
adverse mood reactions may occur (1) during the administration of ovarian hormones in the stabilization 
condition or (2) naturally during the placebo (natural) perimenstrual withdrawal condition. However, because 
the hormone manipulation mimics (i.e., stabilizes) the luteal hormone levels that women naturally 
experience4, the study is not expected to pose any greater risk to participants than what they 
experience in daily life. Furthermore, although withdrawal from exogenous E2/P4 (which will mimic normal 
late luteal phase hormone withdrawal given that exogenous levels will mirror normal luteal physiologic ranges) 
could elicit negative mood changes, these would not be expected to be any more severe than those that would 
otherwise have arisen from normal perimenstrual hormone withdrawal—that is, we will have simply delayed the 
normal withdrawal process. 
 
Suicidality. As detailed above, the population will be recruited to achieve a population of women that is 
simultaneously: (1) experiencing recent suicidal ideation, yet (2) at acceptably low1,2,149 current risk for 


 
 
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suicidal crisis/attempt based on an assessment conducted during a screening visit (see Experimental 
Eligibility Table in later section). Because ovarian hormone changes are implicated in psychiatric symptoms 
in some women39,50, and because such symptoms may increase suicide risk, it is possible that increases in 
suicidality may occur (1) during the administration of ovarian hormones in stabilization conditions or (2) 
naturally during the placebo (natural) perimenstrual withdrawal condition. However, because the hormone 
manipulation mimics (i.e., stabilizes) the normal physiologic range of luteal hormone levels4 that 
women naturally experience, the study is not expected to expose participants to greater risk for 
suicidality than what they experience in daily life.   
 
3) Hormone Side Effects 
 
We do not expect any adverse side effects associated with the hormonal manipulation for the following 
reasons: First, we will be administering the physiologically relevant steroid hormones (estradiol and/or 
progesterone) and not the substituted steroids (such as ethinyl estradiol or norethindrone) present in many oral 
contraceptives and which have been reported to have a potentially more serious profile of side effects176-179. 
Second, prior exogenous hormonal studies (or E2, P4, or a combination) conducted in Dr. Rubinow’s lab at the 
NIH that induced substantially more elevated hormone concentrations and a more precipitous hormone 
withdrawal in women with mood disorders, and no severe psychological adverse events were reported. 
 
SIDE EFFECTS OF ESTRADIOL 
 
The most frequent side effects associated with estradiol use include: 
- breast tenderness (occurs in 29% of patients) 
- abdominal cramps (occurs in 16% of patients) 
- headache (occurs in 13% of patients) 
- edema (swelling) (occurs in 10% of patients) 
- nausea (occurs in 6% of patients) 
- acne (occurs in 3 – 12% of patients) 
- skin rash or irritation may also occur at site where the patch is placed (occurs in 3 - 12% of 
patients) 
 
Rare side effects (<1%) include: 
- jaundice (yellowing of skin) 
- increased blood pressure 
- worsening of migraines or asthma 
- enlargement of uterine fibroids 
- intolerance to contact lenses 
- dizziness 
- changes in appetite and weight 
 
E2 is widely prescribed; given the modest dose and duration administered here, severe adverse events are 
unlikely. Given our plans to administer transdermal E2 to women: (1) for only 14 days, (2) no older than 45 
years of age, (3) who are currently regularly menstruating and medically healthy, and (4) who are at no greater 
than average risk for cancer and venous thromboembolism, the risk of serious adverse events is 
exceedingly low. 
 
 
SIDE EFFECTS OF PROGESTERONE 
 
The most common side effects associated with progesterone include: 
- breast tenderness (occurs in 16% of patients) 
- dizziness (occurs in 24% of patients) 
- abdominal cramping (occurs in 20% of patients) 


 
 
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- headache (occurs in 16% of patients) 
- viral infection (occurs in 12% of patients) 
- joint pain (occurs in 12% of patients) 
- diarrhea (occurs in 8% of patients) 
- menstrual bleeding, sometimes consistent with a heavy menstrual period (occurs in 20-30% of 
patients) 
- drowsiness (occurs in 9% of patients) 
 
Rare (<1%) side effects include: 
- vaginal discharge 
- chest pain 
- abdominal bloating 
 
Progesterone is widely prescribed, with indications including dysfunctional uterine bleeding, endometriosis, 
mastodynia, galactorrhea, and precocious puberty180. In our recent study, a dose of 300 mg of oral micronized 
progesterone (higher than that given in the present study) was given to a sample of women with premenstrual 
mood disturbance and was well tolerated by this sample146. Given the modest dose and duration used in the 
present trial, severe adverse events are unlikely. 
 
4) Confidentiality  
 
A breach of confidentiality could indicate to others a participants’ history of psychiatric symptoms. 
 
5) Venipuncture 
 
Standard risks associated with venipuncture are present during the laboratory testing sessions. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
This is a mechanistic study to determine the role of ovarian hormone changes in constructs that are 
relevant to suicidality. There is no direct benefit to the participants other than the benefit of knowing 
that they are contributing to research on the causes of suicidality.   
 
3 
OBJECTIVES AND PURPOSE 
 
The purpose of this mechanistic study is to experimentally test a pathophysiologic mediational model in 
which late luteal (perimenstrual) E2/P4 withdrawal (vs. experimental luteal E2/P4 stabilization via exogenous 
transdermal E2 and oral micronized P4) increases suicidal desire (via increased hopelessness and negative 
social appraisals) and suicidal action capacity (via reduced inhibitory control and increased threat sensitivity). 
We predict that natural E2/P4 withdrawal (compared to stabilization) will increase reports of suicidal desire 
(partially mediated by task performance indicating increased hopelessness and negative social appraisals) and 
action capacity (partially mediated by task performance indicating decreased inhibitory control and increased 
threat sensitivity). 
 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
 
This is a single-center study; there is no phase designation because it is a mechanistic experiment 
with agents (E2,P4) that is commonly used in clinical practice. 


 
 
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Participants: 30 female outpatients with recent suicidal ideation but low1,2 imminent risk for suicide attempt 
(see Human Subjects section for details) receiving treatment as usual from a mental health provider at UNC 
will be recruited. Women must: be 18 to 45 years of age, have normal menstrual cycles (25-35 days), not 
pregnant (verified with urine screens), breastfeeding, or trying to get pregnant, not taking hormones, no history 
of serious medical illness, normal weight (BMI 18-28 kg/m2), and low risk for thrombotic events (factor V Leiden 
mutation based on family history). Use of psychotropic medications are expected in the majority of participants.  
Most outpatients with suicidality take psychotropic medications; therefore, to increase feasibility and 
generalizability, medication use will be carefully measured daily and covaried in analyses if common enough.  
Psychiatric Diagnoses. Women will undergo initial SCID-I and SCID-II interviews. History of manic episode, 
psychosis (except dissociation), or substance abuse disorder will be exclusionary due to increased risk of suicidal 
crises1,149. Additionally, a self-report history of treatment for postpartum depression or a current diagnosis of 
premenstrual dysphoric disorder will be exclusionary, since these reproductive mood disorders could be 
characterized by a different pathophysiological pattern of sensitivity to ovarian steroid flux150. On the basis of 
work by Dr. Prinstein108, we expect that 50 - 75% of our sample will meet criteria for major or persistent depressive 
disorder, ≥ 50% will meet criteria for BPD, and 
≥ 25% will meet criteria for an anxiety disorder.  
 
Study Design (see figure at right; top = 
naturally occurring cyclicity of E2/P4 under 
placebo, 
bottom 
= 
E2/P4 
withdrawal 
prevention using exogenous E2/P4). THIS IS 
NOT A CLINICAL EFFICACY TRIAL.  However,  
a within-person crossover RCT design with 
transdermal 17β-E2 and oral micronized P4 (or 
placebo) will investigate the pathophysiologic 
role of perimenstrual steroid withdrawal in 
suicidal desire and action capacity. Consenting 
participants will be trained in the protocol, 
including urine ovulation testing (LH surge 
preceding ovulation 24-36 hours), the daily 
phone assessment, and the patch/pill schedule. 
Using a double-blind, within-subject cross-
over design, participants will be randomized as 
to the order in which they receive (1) active 17β-
E2 + P4 or (2) placebo patch/pills. The UNC 
Investigational Drug Services will manage the 
randomization and dispensing of medications. 
During the E2/P4 stabilization condition, for two 
weeks, participants will wear a weekly patch 
(Climara®) delivering 0.10 mg E2/24 hrs—a 
dose tolerated by > 94% of the 200+ women in 
Dr. Girdler’s recent study (NIMHR01087619)— 
and will take oral progesterone (Prometrium®) at a dose of 200 mg (100mg each morning, 100mg each evening). 
A higher dose (300mg/day) was well tolerated by 100% of premenopausal women in Dr. Girdler’s prior research 
(NIMHR01051246). These doses will achieve (stabilize) luteal E2/P4 levels4.  
 
Timing of Hormone Administration. Based on home urine ovulation testing, participants will apply the first 
seven-day transdermal E2 patch (or placebo patch) and begin daily oral P4 (or oral placebo) seven days after 
urine-confirmed ovulation (cycle 1, +7) to coincide with a time in the natural cycle when E2/P4 are elevated. The 
goal of the active E2+P4 manipulation is to extend and maintain the mid-luteal phase hormone profile 
beyond the point in the cycle that would normally be associated with natural E2/P4 withdrawal. In the active 
E2/P4 condition, the luteal phase hormone profile will be maintained for 14 days by applying a new patch on day 
8 (extended luteal phase spanning +7 to +21 in lower panel), preventing natural withdrawal and stabilizing E2/P4 
in physiologic4 luteal range. The placebo condition uses the same patch/pill schedule.  


 
 
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Assessment of Outcomes. Participants will complete phone measures of symptoms and suicidality starting on 
the first day of patches/pills and ending 5 days following the last patch/pill (phone symbols in figure above). Three 
lab sessions will measure mediating constructs using behavioral tasks. In each condition, lab visits will occur on 
days +7, +14, and +22 following ovulation. 
 
 
Primary Windows of Comparison for Hypothesis Testing. To test whether prevention of E2/P4 withdrawal is 
associated with mediating behavioral constructs and suicide risk, we will compare tasks and interviews in LABPL2 
with LABEXP2.  
 
Blinding of Participants and Staff. All study staff performing assessments will remain blinded to condition. The 
natural within-woman variation in menstrual cycle length from one cycle to another will help maintain the 
participant blind.  Few women have regular 28 day cycles, and between-cycle variation up to 8 days is normal4. 
Demand characteristics regarding the impact of hormonal manipulation will be minimized by informing 
participants that women vary a great deal in their responses to hormones, and our current evidence does not 
allow us to predict for certain whether hormones have a positive, negative, or neutral effect on women’s 
symptoms (of note, this is scientifically accurate39). Finally, although some women may become unblinded later 
in the extended hormone phase, work by the mentoring team suggests that pharmacologic delay of menses 
does not influence the course of perimenstrual mood symptoms144. 
 
Lab Construct Measures. Each computerized task is scored using within-task comparisons, controlling for 
experience- or training-related changes in response time. Hopelessness will be measured via the Future 
Thinking Implicit Relational Assessment Procedure (FT-IRAP)151, in which participants respond with true or false 
to pairings between “I expect” and “I don’t expect” with sets of negative (e.g., worry, sadness) and positive (e.g., 
enjoyment, happiness) events. Greater latency to optimistic/hopeful, and lower latency to pessimistic/hopeless 
pairings indicate implicit hopelessness151. Validity: Performance predicts clinical hopelessness and 
depression151. Negative Social Appraisals will be measured using the Social Acceptance-Rejection Implicit 
Association Test (SAR-IAT)152, in which participants respond to pairings of self words (e.g., I, me) and other 
words (e.g., them, you) with words indicating social acceptance (e.g., included) or social rejection (e.g., rejected). 
Response times to pairings indicate the strength of implicit self-with-acceptance or self-with-rejection 
associations. Validity: Performance predicts explicit social appraisals and heightened negative affect in social 
interactions per clinical interviews152. Inhibitory Control will be measured using performance on the Stop-Signal 
Task (SST)153, an index of the ability to withhold a prepotent response. Validity: Performance predicts prefrontal 
cortex function and lower impulsive clinical outcomes153. Threat Sensitivity will be measured as attentional bias 
for threat pictures on a Dot Probe Task (DPT)154. Validity: Attentional bias to threat on this task is linked to anxiety 
disorders155 and multimodal indices of threat sensitivity in daily life154,156.  
 
Daily Telephone Symptom Measures (PRIMARY AND SECONDARY ENDPOINTS): Depressive Symptoms 
and Hopelessness using the 10-item short form of the CES-D161 and the Beck Hopelessness Scale162, Anxiety 
Symptoms (reflecting Threat Sensitivity) using the 6-item short form of the Patient-Reported Outcome 
Measurement Information System (PROMIS) Anxiety scale163; Impulsive Symptoms using a five item version 
of the UPPS-P Lack of Premeditation (i.e., classic impulsivity) subscale158; and Rejection Sensitivity 
Symptoms (reflecting social appraisals) using two items with high item-total correlations from the Social 
Evaluation subscale of the State Self-Esteem Scale157. Each of these inventories has been extensively validated 
for the measurement of the target construct. Suicidal desire and action capacity will be measured daily using 
a shortened version of the SITBI160.  
 
Participant Safety: Emergent changes in suicidality will be managed using the structured University of 
Washington Risk Assessment and Management Protocol (UWRAP)3,164, a safety protocol recommended by 
NIMH for RCTs since it allows for the safe study of individuals with suicidality3. If imminent risk for suicide 
emerges and cannot be satisfactorily managed by the UWRAP protocol (as determined by Dr. Prinstein), the 
protocol for discontinuation will be followed. However, because the manipulation mimics luteal E2/P4 levels that 


 
 
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women naturally experience, the hormonal manipulation is not expected to pose greater risk than a normal4 
menstrual cycle—the risk will simply be shifted in the stabilization condition. 
 
 
4.2.1 PRIMARY ENDPOINT 
 
The primary endpoints (described below) of this mechanistic study are suicidal ideation and planning score 
differences between placebo days and stabilization days on the SITBI interview. These were chosen given 
their strong predictive validity in epidemiological studies.  
 
(1) Mean Within-Person Condition Difference (7 final placebo days – 7 final stabilization days) of SITB 
Suicidal Ideation subscale score  
 
(2) Mean Within-Person Condition Difference (7 final placebo days – 7 final stabilization days) of SITB 
Suicidal Planning subscale score  
 
 
4.2.2 SECONDARY ENDPOINTS 
 
The secondary endpoints of this study include the daily telephone measures as follows:  
 
(6) Mean Within-Person Condition Difference (7 final placebo days – 7 final stabilization days) of BHI 
Hopelessness Score  
 
(7) Mean Within-Person Condition Difference (7 final placebo days – 7 final stabilization days) of CES-D 
Depression Total Score  
 
 
(8) Mean Within-Person Condition Difference (7 final placebo days – 7 final stabilization days) of UPPS-P 
Lack of Premeditation Impulsivity subscale 
 
(9) Mean Within-Person Condition Difference (7 final placebo days – 7 final stabilization days) of PROMIS 
Anxiety Total Score 
 
(10) 
Mean Within-Person Condition Difference (7 final placebo days – 7 final stabilization days) of 
SSES Social Evaluation/ Rejection Sensitivity subscale 
 
 
4.2.3 EXPLORATORY ENDPOINTS 
 
None. 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following general criteria:  
• 
Provision of signed and dated informed consent form  
• 
Stated willingness to comply with all study procedures and availability for the duration of the study  
• 
Ability to take oral medication and be willing to adhere to the medication regimen  


 
 
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To be eligible for participation, an individual must also meet all of these study-specific following criteria. 
 
1. Must be biologically female and between the ages of 18-45 years.  
o Justification: Women younger than 18 or older than 45 may have inconsistent menstrual 
cycles or may be postmenopausal and therefore no longer cycling. 
 
2. Must have normal menstrual cycles between 25 and 35 days. 
o Justification: Abnormal menstrual cycle lengths or variability in lengths could introduce error 
variance into the experiment, and could reduce confidence regarding the timing of the 
experimental manipulation to cycle events. 
 
3. Must be under the current care of an outpatient mental health provider. 
o Justification: Because we intend to recruit women with current suicidality, engagement with a 
mental health provider is required as a protective measure to ensure that participants have 
access to treatment if needed. 
 
4. If the woman has children, she must be at least 1 year postpartum. 
o Justification: The postpartum period can be characterized by altered hormone levels and 
changes; therefore, postpartum women may introduce error variance into the experiment. 
 
5. Must be of normal weight (BMI between 18-29 kg/m2); measured at the enrollment visit. 
o Justification: Responses to doses of hormones may vary by BMI and risk for thromboembolic 
events with hormone use increases in obese women. 
 
6. Must report at least some recent suicidal ideation (in the past month) at enrollment. 
 
• 
Justification: As reviewed in the research strategy, the purpose of the study is to examine the 
impact of natural perimenstrual hormone withdrawal (vs. prevention of hormone 
withdrawal/stabilization of E2/P4) on within-person changes in suicide risk. The present 
sampling strategy ensures generalizability3 of our findings to clinical populations of interest 
and will also prevent a floor effect (i.e., zero-inflation of daily outcome measures and 
associated limitations in power to detect effects) on primary daily outcome measures (e.g., 
mediating behavioral constructs, suicidality).  
 
7. Must be categorized as having acceptably low imminent risk for suicidal crisis/attempt according 
to established clinical and research guidelines149 (see Eligibility Table), which have been adapted for 
the current study in collaboration with the co-mentor, Dr. Prinstein. As co-mentor Dr. Prinstein notes in 
his 2014 methodological paper on research-based suicide risk assessment2, evaluation of imminent 
risk of suicidal crisis/attempt is a complex clinical task, requiring integrative consideration of a variety of 
factors (including: general clinical presentation, ideation severity, frequency, recency, and associated 
consideration/intent; access to suicidal means; previous attempts and gestures; presence of suicidal 
planning, recent stressors, frequency of contact with mental health provider; and presence of social 
support). Therefore, our specific criteria for delineating whether a participant is eligible are based on an 
evidence-based determination2,149 that the participant is at acceptably low imminent risk of suicidal 
crisis/attempt. These decisions will be based on responses to a variety of questions from the SITBI 
and Severity of Suicidal Ideation Interview (clinical interviews at the beginning of an enrollment visit). 
 
o Justification: Individuals with current suicidality are not necessarily at imminent risk for 
suicidal crises/attempt (i.e., their risk is manageable on an outpatient basis through frequent 
clinical contact, such as the daily calls in the present study). Because the hormone protocol 
simply prolongs the physiologic luteal hormone profile, they are not expected to expose 
participants to additional risk of suicidal crisis beyond what they would naturally experience 
during their typical monthly menstrual cycles. However, out of an abundance of caution, we will 


 
 
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exclude women with elevated imminent risk for suicidal crisis/attempt (determined by 
structured interview and established guidelines2,149). Individuals with histories of suicidality often 
have ongoing, habitual thoughts about death or suicide that are highly distinguishable from 
imminent risk for suicide attempt1,149,166. In further support of this notion and of the feasibility 
of recruiting this population, it should be mentioned that up to 1/3 of the American population 
experiences suicidal ideation at some point in their lives166, yet less than .01% die by suicide 
each year149,166.  
 
 
 
 
 
SPECIFICS OF SUICIDE RISK-RELATED ELIGIBILITY CRITERIA  
 
The study will include only women with current suicidal ideation (past-month endorsement of suicidal 
ideation) in order to maximize generalizability to our clinical population of interest. We hypothesize that natural 
perimenstrual withdrawal from ovarian hormones will be associated with significant but transient shifts in 
continuously-estimated suicide risk that are not expected to escalate to the level of suicidal 
crisis/attempt (due to the exclusion of certain women at highest risk for attempt, as noted below). In order to 
minimize the risk of suicidal crises during the study, we will exclude women who meet evidence-based 
criteria2,149 for imminent risk of acute suicidal crisis/attempt. 
 
The goal of these exclusion/inclusion criteria is to minimize the risk that a participating woman will 
demonstrate imminent risk of suicidal crisis/attempt during the study. The determination of acceptably low 
current risk of suicidal crisis/attempt will be carried out in multiple steps, as follows: 
 
1. First, women must pass a phone screen in which they will report on their previous psychiatric 
diagnoses and recent history of suicide attempts. At that juncture, the following criteria will be applied:      
a. A woman will be excluded if she reports a suicide attempt or any concrete suicidal planning in 
the past 3 months, as the majority of repeated attempts occur within the first three months 
following an initial attempt1,149. 
b. A woman will be excluded if she reports a history of more than one suicide attempt, as multiple 
attempts represent a uniquely potent risk factor for additional suicidal crises/attempts1,149. 
c. A woman will be excluded (and referred) if she reports that she does not currently visit a mental 
health provider (psychiatrist, therapist) at least once every 3 months1.  
d. A woman will be excluded if she reports any extreme external stressors (e.g., death of a loved 
one, loss of employment) in the past month, as extreme stressors drastically increase the risk of 
suicidal crisis1,149. 
e. A woman will be excluded if she reports a history of clinical diagnosis with manic episode, 
psychotic symptoms, or substance use disorder, as these disorders reduce predictability and 
increase likelihood of suicidal crises/attempt149.  
 
2. Second, women must pass an in-person eligibility screening at the beginning of an enrollment visit, in 
which they will complete a clinical interview designed to more thoroughly assess the risk factors 
described in 1a-1e above, as well as additional determinants of suicide risk outlined in Eligibility Table. 
a. Eligibility criteria in 1a-1e above will again be re-assessed and applied.  
b. Using a clinical interview based on the SITBI interview160 and the Scale for Suicidal Ideation 
interview168, the PI will evaluate each woman on a variety of risk factors for suicidal crisis and 
evaluate whether a woman has acceptably low1,2,149 imminent risk of suicidal crisis/attempt using 
the decision rules described in the leftmost column in Eligibility Table and summarized below: 
• 
The evidence-based determination of acceptably low risk1,2,149 of suicidal 
crisis/attempt will be based on the count of positive findings in each Row of 
Eligibility Table (see next page), as follows: No positive findings in Row 5; No 


 
 
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greater than 1 positive finding in Row 4; No greater than 2 total positive findings 
in Rows 3 + 4; No greater than 3 total positive findings in Rows 2, 3, and 4. 
 
3. Finally, Dr. Eisenlohr-Moul (the PI) will review the results of each eligibility visit interview with Dr. 
Prinstein at weekly meetings (see Training Plan and Co-Mentor Letter) to verify that the individual 
demonstrates acceptably low1,2,149 imminent risk of suicidal crisis/attempt before approving participation 
in the experiment. Should Drs. Eisenlohr-Moul and Prinstein determine the patient is at imminent risk of 
suicidal crisis/attempt despite meeting the criteria described previously, the patient will not continue 
with participation. However, should Dr. Prinstein agree that the patient indeed demonstrates acceptably 
low1,2,149 risk of suicidal crisis/attempt as outlined in Eligibility Table, the participant will continue with 
randomization and participation in the study. 
 
4. Note that ongoing participant suicide risk monitoring and management is described in later sections. 


 
 
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EXPERIMENTAL ELIGIBILITY TABLE 
 
The goal of the suicide-related exclusion/inclusion criteria (outlined below) for the study is to minimize the risk that a participant will experience an 
acute suicidal crisis or attempt suicide during the study. Evidence-based criteria were developed in collaboration with the co-mentor, Dr. 
Prinstein1,2,149. History of mania, psychosis, or substance abuse disorder will also be exclusionary. Table notes: Recent = In the past month. MHP = 
Mental Health Provider. 1SITBI items 3a, 3b, 4a, 4b, 4c. 2SITBI items 1a, 1b, 1c, 1f, 2c. 3SITBI items 2a, 2b. 
 
 
ROW 
Suicide 
Attempts1 
Suicidal Thoughts2 
Recency 
of Last 
Suicidal 
Planning3 
Current 
Access to 
Means 
Recent 
Stressors/
Loss 
Current 
Frequency 
of MHP 
Contact 
Current 
Social 
Support 
Number 
Recency 
 
Recency 
 
Recent 
Frequency 
Recent 
Severity 
Recent 
Intent 
 
 
 
 
 
1 
Never 
Never 
In past 
year 
Less than 
monthly 
1f=1 
2c=1 
Never 
No Access 
to Means 
None 
>1x/ 
month 
Multiple 
Strong 
Supporter
s 
2 
No more than 3 
total positive 
findings allowed 
in Rows 2,3, +4 
Any 
gesture 
or NSSI, 
no 
attempt 
In past 2 
years 
In past 
month 
~1x/ 
month 
1f=2 
2c=2 
>2 years 
ago 
 
Extreme 
Stressors in 
past year 
~1x/ 
month 
One 
Strong 
Supporter 
or multiple 
supports 
3 
No more than 2 
total positive 
findings allowed 
in Rows 3 + 4 
1 
aborted 
attempt 
in past 
year 
In past 
week 
~1x/ week 
1f=3 
2c=3 
1-2 years 
ago 
Access to 
Nonspecific 
or  
Unfeasible 
means 
Extreme 
Stressors in 
last 3 
months 
~1/ 
2 months 
Very 
Limited 
Support 
4 
No more than 1 
positive finding 
allowed in Row 4 
1 
attempt 
In past 6 
months 
Now 
>1x/ 
week 
1f=4 
2c=4 
3 months 
to 1 year 
ago 
Access to 
Specific, 
Feasible 
Means 
Extreme 
Stressors in 
last 1-2 
months 
~1x/ 
3 months 
No 
Support 
5  
No positive 
findings allowed 
in Row 5 
>1 
attempt 
In past 3 
months 
 
 
 
 
<3 months 
ago 
 
Extreme 
Stressors in 
last month 
<1x/ 
3 months 
 


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5.2 
PARTICIPANT EXCLUSION CRITERIA 
 
Any individual meeting any of the following exclusion criteria at baseline will be 
excluded from the study: 
 
1. Must not be pregnant, breastfeeding, or trying to become pregnant. Pregnancy 
status will be confirmed using urine pregnancy test at the enrollment visit and again at 
the first visit of the second condition. Women will be encouraged to use a barrier method 
of birth control during the study. 
o Justification: Administration of ovarian hormones to a pregnant woman could 
negatively influence the pregnancy in a variety of ways, including risks to the 
health of the fetus. 
 
2. Must not be taking any form of exogenous hormones or IUD, and must have ended 
previous use of hormonal preparations at least one month prior to the study. 
o Justification: The use of additional exogenous hormones poses safety risks and 
would undermine experimental control of hormones.  
o Women will be required to use licensed barrier methods of contraception 
during study participation; if they are unable to commit to this 
responsibility, they will not be eligible for participation. 
 
8. Must report no personal history of any chronic medical condition, 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. 
o Justification: Administration of exogenous hormones to women with these 
chronic medical conditions may increase the risk of an adverse health-related 
response to hormones. Further, the purpose of the present study is to determine 
the impact of hormonal stabilization (vs. natural withdrawal) in otherwise 
physically healthy women.  
 
9. Must not currently smoke cigarettes. 
o Justification: Administration of ovarian hormones to women who smoke may 
increase the risk of thromboembolic events.  
 
10. Must not report a history of clinical diagnosis of postpartum depression or premenstrual 
dysphoric disorder (Note: PMDD diagnosis must have been made based on prospective 
daily ratings).  
o Justification: Some evidence would suggest that the pattern of perimenstrual 
symptoms that have been linked with these reproductive mood disorders could 
differ meaningfully39 from that which we be expect in the more general clinical 
population of women with suicidality8. Because these distinctions are not yet 
clear, women with a self-reported history of clinical diagnosis with these 
disorders will be excluded.  
 
11. Must not report any history of manic episode, psychotic symptoms, or substance use 
disorder.  
o Justification: These factors are known sources of variability in suicidality and 
would therefore introduce error into our models as well as increasing the risk that 
a participant would experience a suicidal crisis during the study1,149.  


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5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment and Informed Consent 
 
To ensure adequate enrollment of an adequate number of participants, we will employ a number 
of recruitment strategies. First, Participants will be recruited from the University of North 
Carolina at Chapel Hill Outpatient Psychiatry Clinic, where the PI currently follows 
psychotherapy patients and therefore have access to recruitment pathways. Second, we will 
advertise to the Raleigh, Durham, Chapel Hill (i.e., the “Triangle”) community using email and 
listserv advertisements (sent to the UNC-Chapel Hill community), flyers in local businesses and 
buses, and radio/newspaper/website ads.  
 
Potential participants will complete initial eligibility screening by telephone and a secure online 
questionnaire. 
 
No more information will be asked of participants than necessary to obtain eligibility information 
and to contact those who appear to be eligible to schedule a screening/enrollment visit. At this 
initial visit, the PI (Dr. Eisenlohr-Moul) will obtain written informed consent for further screening 
regarding suicidality from those individuals who pass the initial telephone and questionnaire 
screenings and are interested in participating. This consent will inform participants regarding the 
nature of the questions to be asked. If the participant consents, the Self-Injurious Thoughts and 
Behaviors Interview160 and the Scale for Suicidal Ideation Interviews168 will be administered. If 
the participant is not eligible for the study following the screening (see details above), they will 
be dismissed and referred for treatment as necessary. If they are eligible, Dr. Eisenlohr-Moul 
will obtain additional written informed consent for participation in the larger study (i.e., the 
screening visit will become the enrollment visit). During the consenting process for the larger 
study, all of the applicable consent forms will be reviewed with each individual, and they will be 
given as much time as they would like to discuss their participation with their significant others 
and decide whether to participate.  
 
INCLUSION OF WOMEN AND MINORITIES 
 
Men will not be included in this study, given the stated purpose of examining ovarian 
hormone withdrawal as a mechanism of suicidal risk in women. 45 women will be included in 
the study. 
The UNC Center for Women’s Mood Disorders has a strong commitment to the 
enrollment of minority women in research projects, and this commitment will be reflected in this 
study. As shown below, the ethnic and racial composition of the population from which subjects 
will be recruited, including Orange, Durham, and Wake counties, is similar to the population of 
the United States as a whole.  
 
 
 
 
 
 
 
 
 
 


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Race/Ethnicity Wake 
Durham 
Orange 
Adjusted 
Average 
White  
70% 
54% 
78% 
69% 
Black or 
African 
American  
21% 
39% 
12% 
24% 
American 
Indian/Alaska 
Native  
1% 
1% 
1% 
1% 
Asian  
6% 
5% 
7% 
6% 
Hispanic or 
Latino Origin  
10% 
14% 
8% 
11% 
 
 
The PI plans to recruit similar proportions of ethnic and racial minorities for the 
study. We have conservatively estimated our ability to recruit a sample that is 76% White, 
20% Black or African American, 4% Asian, and with 8% identifying as Hispanic or Latina.   
 
Recruitment Plan for Minorities : We realize, however, that specialized efforts will be needed to 
meet these goals.  Because minorities underutilize mental health care, the PI will also advertise 
in the community to recruit subjects who are currently experiencing emotional symptoms. Dr. 
Girdler, primary mentor, has a long-standing track record of successful recruitment of African 
Americans (our largest minority population) into clinical research studies.  In her most recent 
ethnic differences research (RO1-DA13705), she was successful at recruiting over 125 African 
American men and women (50% of the entire sample) and in each of her current studies (RO1s 
MH087619 and MH099076), 30% of the women enrolled identify as African American.   We will 
employ the strategies that have proven successful in her prior studies.  The single most 
effective strategy involves the use of minority research staff in the recruitment and retention 
process.  Other strategies involve the use of culturally sensitive language in advertisements, 
including assurances that the study involves no experimental drugs or devices.  We will also 
advertise in periodicals targeting African American populations and work with community-based 
minority programs.  Statistics will be kept throughout the study documenting recruitment 
strategy and enrollment rates, allowing the PIS to adjust initiatives accordingly.  Should 
additional initiatives be necessary, we will work directly with leaders from the African American 
community. 
 
JUSTIFICATION FOR INCLUSION OF INDIVIDUALS WITH CURRENT SUICIDALITY 
 
As reviewed in the study background and rationale, the purpose of the study is to examine the 
impact of natural perimenstrual hormone withdrawal (vs. prevention of hormone 
withdrawal/stabilization of E2/P4) on within-person changes in suicide risk. The present 
sampling strategy ensures generalizability3 of our findings to clinical populations of interest 
(i.e., not simply depressed women, but those with suicidality) and will also prevent a floor 
effect (i.e., zero-inflation of daily outcome measures and associated limitations in power to 
detect effects) on primary daily outcome measures (e.g., mediating behavioral constructs, 
suicidality).  


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Individuals with current suicidality are not necessarily at imminent risk for suicidal 
crises/attempt (i.e., their risk is manageable on an outpatient basis through frequent clinical 
contact, such as the daily calls in the present study). Because the hormone protocol simply 
prolongs the physiologic luteal hormone profile, it is not expected to expose participants to 
additional risk of suicidal crisis beyond what they would naturally experience during their typical 
monthly menstrual cycles. However, out of an abundance of caution, we will exclude women 
with elevated imminent risk for suicidal crisis/attempt (determined by structured interview 
and established guidelines2,149). Individuals with histories of suicidality often have ongoing, 
habitual thoughts about death or suicide that are highly distinguishable from imminent risk for 
suicide attempt1,149,166. In further support of this notion and of the feasibility of recruiting this 
population, it should be mentioned that up to 1/3 of the American population experiences 
suicidal ideation at some point in their lives166, yet less than .01% die by suicide each year149,166.  
 
RETENTION OF INDIVIDUALS WITH SUICIDALITY 
 
Although a variety of exclusion criteria will be applied, the PIs recent work has prepared her to 
recruit, retain, and maintain the safety of108 women with suicidal ideation but low2,149 imminent risk 
of attempt. Furthermore, the majority of individuals with suicidal ideation do not evidence imminent 
risk for suicide attempt2,166, supporting the feasibility of recruiting from this population. With regard 
to retention, the PI has demonstrated the capacity to recruit and retain women with BPD with 
suicidal ideation, and participants with BPD in her recent study have completed 85% of daily email 
surveys; given larger incentives for shorter daily contacts, we expect a higher response rate. The 
PI has also worked on recruitment and retention (using the same psychiatric exclusion criteria) in 
her new clinical fellow role with Dr. Prinstein, who has great success in the recruitment, phone 
engagement, and retention of suicidal outpatients108. Empirically-supported strategies167 for 
retention will include study branding, frequent contact, monetary rewards, and graduated 
compensation schedules.  
 
 
Study subjects will receive the following monetary incentives: 
 
$100 pay for one enrollment visit 
 
$50 pay for each laboratory testing session x 6 laboratory sessions = $300 possible testing visit 
pay 
 
$200 pay for daily phone calls (prorated at $5 per day if subject withdraws) 
 
= For a total possible compensation of $600  
 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Participants are free to withdraw from participation in the study at any time upon 
request. An investigator may terminate participation in the study if:  
• 
Any clinical adverse event (AE), or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant as 
determined by the DSMB or Dr. Eisenlohr-Moul in collaboration with Dr. Prinstein 


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(severe mood deterioration, severe changes in suicidality), Dr. Rubinow (hormonal side 
effects). Dr. Rubinow may consult Dr. Young with regard to gynecologic issues as 
necessary.  
 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
 
 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
 
Protocol for Discontinuation and Referral. If a participant shows emergence of severe mood 
symptoms or greater than low risk of suicide attempt, the UWRAP protocol for assessing and 
managing suicide risk will be closely followed, supervised by Dr. Eisenlohr-Moul and Dr. 
Prinstein (see Appendix for UWRAP). However, if a participant is judged to be at imminent risk 
of suicide and therefore in need of immediate hospitalization, the participant will be immediately 
discontinued from participation and hospitalized. Our offices are in close proximity to UNC 
emergency department, and participants requiring immediate emergency care can easily be 
transferred there. An immediate follow-up phone call to the participant’s mental health provider 
alerting them to the change in symptoms (see information below regarding consent to provider-
researcher communication) will occur immediately. If the participant is taking study medication 
currently, Dr. Rubinow will immediately be contacted and he will break the blind. If it is revealed 
that the participant is currently in the placebo condition, he will take no further action. However, 
if it is revealed that the participant was currently in an active hormone stabilization condition, he 
will oversee the subject’s discontinuation of the exogenous hormone according to his best 
clinical judgment.  
 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 
At six month intervals, the study biostatistician (Dr. Xia) will test whether there are significant 
differences in the occurrence of moderate, severe, and serious AEs in the placebo vs. the 
experimental condition with alpha set at .05. These results will be provided to the Data Safety 
and Monitoring Board (DSMB) along with the summary report of enrollment.  
 
Administration of study agent will be halted when three serious AEs* determined to be 
“probably related” (i.e., with new onset during study patches/pills) are observed. The PI 
will immediately notify the DSMB when this occurs. The DSMB will notify the study sponsor and 
investigators immediately when the third severe event is reported and enrollment screens will 
stop accepting new study participants. Dr. Xia will again perform an unblinded statistical 
analysis to further determine whether active study medication (E2/P4) is significantly 
related to greater risk of AEs relative to placebo. All requested documentation will be 
provided to the DSMB. The DSMB will convene an ad hoc meeting by teleconference or in 
writing as soon as possible. The DSMB will provide recommendations for proceeding with the 
study to the PI and the NIH. The study sponsor will inform all appropriate regulatory agencies of 
the temporary halt and the disposition of the study. 
 
The DSMB will consider stopping the entire study based on the results of the statistical tests 
provided by Dr. Xia: specifically, if the experimental hormone stabilization condition is 
associated with greater risk of severe or serious AEs than placebo, and there is evidence (as 
determined by David Rubinow) that such AEs are causally related to the study drug, the study 


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will be terminated.  
 
*Notable examples of serious adverse events in the present study include development 
of a venous thromboembolism or suicide attempt.  
 
 
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
 
Both Climara patches (transdermal E2) and Prometrium pills (oral micronized P4) will be 
acquired through UNC Investigational Drug Services from their respective manufacturers.  
 
IDS will order climara + prometrium, placebo patches have been shipped, donated from Wisner.  
 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Please see attached inserts for information about active Climara patches (transdermal E2) and 
Prometrium (oral micronized P4). Both transdermal E2 and oral micronized P4 are readily 
commercially available. Placebo patches and pills (both in stock at UNC IDS) are formulated 
and designed to be identical in appearance to these agents; all packaging and blinding will be 
accomplished via UNC Investigational Drug Services.  
 
6.1.3 PRODUCT STORAGE AND STABILITY 
 
Both Climara and Prometrium can be stored at room temperature for the duration of an 
individual’s study participation. Participants will be instructed to avoid exposing study 
drugs to extreme temperatures or humidity. More specific information about storage and 
stability can also be found in the attached inserts for Climara and Prometrium.  
 
6.1.4 PREPARATION 
 
All preparation will be handled by UNC Investigational Drug Services (IDS), who will blind and 
mask the study drugs. No further preparation will be required by study staff or participants.  
 
6.1.5 DOSING AND ADMINISTRATION 
 
Dosages of E2 and P4 will be fixed. Dosages will not be tied to meals, but will be 12 hours apart 
in the morning and evening. 
6.1.6 ROUTE OF ADMINISTRATION 
 
E2 will be administered via transdermal patch. Micronized P4 will be administered orally in pill 
form. 
 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 


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In the experimental arm, the dosages will be fixed and not changed.  
 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
 
If the PI and her supervisors determine that a participant must be discontinued from the protocol 
(see Section 5.4.2), Dr. Rubinow will be unblinded via IDS. If the participant was on active 
E2/P4, Dr. Rubinow will supervise the subject’s discontinuation from E2/P4. Regardless of the 
condition the participant was in, the PI will continue to follow the participant until appropriate 
clinical care is administered (e.g., hospitalization for suicidality). 
 
6.1.9 DURATION OF THERAPY 
 
The planned duration of active treatment is 14 days. All days in which participants use patches 
and pills will be utilized in multilevel modeling analyses, which accommodate 
unbalanced/missing data.  
 
6.1.10 TRACKING OF DOSE 
 
For patches (E2): E2 patches will be applied (day +7 following ovulation) and changed (day 
+14 following ovulation) in the laboratory; therefore, no compliance issues are anticipated for 
E2.  One extra patch will be given to each participant in the case that the patch falls off. All used 
patches will be brought to the lab so that use of patches can be monitored. 
For pills (P4): at the first lab visit, study staff will work with participants to develop individualized 
methods for reminding the participant to take twice-daily study pills, including but not limited to 
email reminders, phone call reminders, text reminders, app-based reminders (with data stored 
locally only), pill charts, calendar reminders, and stimulus control (e.g., putting study medication 
on bedside table. Women will bring in pill bottles to each visit so compliance can be monitored.  
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
 
Not applicable.  
 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
 
Research staff pick up agents from IDS and distribute to subjects as outlined in the 
study schedule below. All unused pills and patches will be returned to study staff, who 
will return them to IDS. IDS will dispose of unused materials according to regulations. 
 
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  
 
PHONE SCREENING 


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Variable 
Interview 
Measure 
Self-Report 
Measure 
Task Measure 
Inclusion/Exclusion Criteria 
x 
- 
- 
Psychiatric Diagnosis 
Self-
reported 
Previous 
Diagnosis 
- 
- 
Suicidality 
Abbreviated 
SITBI 
- 
- 
 
 
ENROLLMENT VISIT – 1 VISIT @ 1.5 HRS 
• Timing: Can occur at any time provided that it allows for the participant to 
complete the protocol in the term of IRB approval. 
• Assessments Administered (see section 4.1 for Abbreviations): 
 
Variable 
Interview 
Measure 
Self-Report 
Measure 
Task Measure 
Vitals 
- 
- 
Height/Weight 
Urine Pregnancy Screen 
- 
- 
x 
Inclusion/Exclusion Criteria 
x 
 
 
Psychiatric Diagnosis 
SCID 
- 
- 
Suicidality 
Full SITBI 
- 
- 
Depression 
- 
CESD 
- 
Hopelessness 
- 
BHI 
- 
Inhibitory Control 
- 
UPPS-P 
- 
Threat Sensitivity 
- 
STAI 
- 
Negative Social Appraisals 
- 
SSES 
- 
 
LABORATORY TESTING VISITS – 6 VISITS @ 1.5 HRS 
• Timing: The three laboratory visits for each condition will occur on days +7, +14, 
and +22 following positive ovulation test (day 0). The acceptable windows will be 
+/- 2 days in either direction for each visit.  
• Assessments Administered (see section 4.1 for Abbreviations): 
 
Variable 
Interview 
Measure 
Self-Report 
Measure 
Task Measure 
Urine Pregnancy Screen 
(3rd visit only) 
- 
- 
x 
Blood Sample (10 ml tube) 
- 
- 
Serum E2/P4 
Suicidality 
Full SITBI 
- 
- 
Depression 
- 
CESD 
- 
Hopelessness 
- 
BHI 
FT-IRAP 
Inhibitory Control 
- 
UPPS-P 
SST 
Threat Sensitivity 
- 
STAI 
DPT 


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Negative Social Appraisals 
- 
SSES 
SAR-IAT 
Side Effects and 
Compliance Monitoring 
X 
- 
- 
 
DEBRIEFING VISIT – 30 MINUTES 
 
• Timing: Debriefing will occur within a 15 day window following completion of the 
second condition.  
• Individual results will not be reported to the patient. 
• Referral to original care provider will be facilitated as necessary. 
• Assessments Administered (see section 4.1 for Abbreviations): 
 
Variable 
Interview 
Measure 
Self-Report 
Measure 
Task Measure 
Final Suicide Risk 
Assessment 
Full SITBI 
- 
- 
 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
 
Although the LRAP/UWRAP dictates the provision of basic supportive conversation and other 
simple interventions to reduce imminent risk in the context of increased suicidality, participants 
are expected to utilize their mental health provider for any treatment needs that arise during the 
course of the study. Therefore, participation will require that the participant consents to phone 
contact between the PI and their current mental health provider in two circumstances: (1) one 
standard phone contact occurring prior to engagement in the first condition in which the PI 
describes the experiment and explains the protocol for daily risk assessment and 
discontinuation of participation should it be necessary; and (2) as-needed phone contact in the 
event that the participant must be discontinued to alert the provider to the severe change in 
mood symptoms or suicidality. 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
 
A point-of-care urine pregnancy test will be completed in our laboratory on site on two 
occasions: prior to randomization at the enrollment visit, and at the third study visit of the first 
condition. 
 
At all 6 laboratory assessments during active treatment with placebo or E2/P4, women will 
provide 10ml blood samples to be assayed for E2/P4 to evaluate the success of the hormone 
in achieving stable luteal phase levels of E2/P4. Cheryl Walker’s laboratory at UNC will conduct 
assays. Storage onsite will be handled by medical technician Joe Hodges in Dr. Susan Girdler’s 
laboratory.  
 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
 
Blood will be centrifuged and serum will be aliquotted into storage tubes and stored in a 
-80 F freezer in Dr. Girdler’s lab. Standard freezer-proof labels will indicate participant 


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ID and study session. These will be transported under dry ice conditions to Dr. Cheryl 
Walker’s laboratory in batches. Following assay, any additional serum will be stored in 
Dr. Girdler’s laboratory.  
 
7.2.4 SPECIMEN SHIPMENT 
 
Serum transport will be handled by Joe Hodges to Cheryl Walker’s Bioendocrine lab 
under dry ice conditions. Samples will be sent in batches when there are enough 
aliquots to support purchase of RIA kits.  
 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
 
The screening procedures described below must take place prior to the enrollment visit; 
because all information about eligibility obtained during the phone screen is confirmed at the 
enrollment visit, there is no expiration of screening procedures after which they must be 
repeated. 
 
Women will be recruited primarily through chart review at the UNC outpatient psychiatry clinic; 
only those women agreeing to be recontacted for research procedures can be contacted. Dr. 
Eisenlohr-Moul will identify women via chart review who may be eligible for the study, and 
contact them to explain the study, and conduct phone screening in interested individuals. 
 
Following verbal consent, verbal phone screening will include verbal assessment of all 
inclusion/exclusion criteria described above, including assessment of recent suicidality using the 
shortened SITBI.  
 
7.3.2 ENROLLMENT/BASELINE 
 
Following recruitment screening via telephone, interested individuals will schedule and attend 
an enrollment visit at which they will provide informed consent and be further assessed for 
eligibility; assessment for eligibility includes assessment of height and weight (BMI), urine HcG 
pregnancy test, consent to contact their mental health provider at appropriate intervals for study 
participation, and other self-reported inclusion/exclusion criteria (including appropriate level of 
suicide risk on the SITBI-- see information in section 5.1). If ineligible, they will be referred back 
to their mental health provider and receive payment for the enrollment visit. If eligibility is 
confirmed, they will be further characterized using the SCID-I and SCID-II and complete various 
psychosocial questionnaires. In addition, they will be trained in the protocol for urine ovulation 
testing, daily telephone assessments, and the patch/pill administration schedule. Participants 
will be randomized to one of two possible condition orders at that time.  
 
Pregnancy test must be negative in order for the participant to continue with the study. The 
study agent will not be administered until Lab assessment 1 (i.e., not at baseline/enrollment).  
 
7.3.3 FOLLOW-UP  
 


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Following the baseline/enrollment visit, women will remain in contact with study staff 
and will begin ovulation testing as instructed. When ovulation testing is positive (day 0), 
the participant will contact the study staff to schedule the first three laboratory 
assessment visits (visits for condition 1) on days +7, +14, and +22. All laboratory 
assessment visits are identical in structure and content, with the singular exception that 
the third laboratory visit in the first condition will include a pregnancy test that must be 
negative prior to starting the second condition. When the first condition is completed 
and the second pregnancy test is negative at the third laboratory visit, women will again 
remain in contact with study staff to schedule ovulation testing in the next menstrual 
cycle. Once again, when ovulation is confirmed (day 0), the final 3 laboratory 
assessments (for condition 2) will be scheduled on days +7, +14, and +22. These visits 
may be scheduled up to +/-2 days in either direction. 
 
• Follow-Up Assessments Administered (see section 4.1 for Abbreviations): 
 
Variable 
Interview 
Measure 
Self-Report 
Measure 
Task Measure 
Vitals 
- 
- 
Weight 
Urine Pregnancy Screen 
(3rd follow-up only) 
- 
- 
x 
Blood Sample (10 ml tube) 
- 
- 
Serum E2/P4 
Suicidality 
Full SITBI 
- 
- 
Depression 
- 
CESD 
- 
Hopelessness 
- 
BHI 
FT-IRAP 
Inhibitory Control 
- 
UPPS-P 
SST 
Threat Sensitivity 
- 
STAI 
DPT 
Negative Social Appraisals 
- 
SSES 
SAR-IAT 
Side Effects, AEs, and 
Compliance Monitoring 
X 
- 
- 
 
Follow-Up Timeline: 
 
Condition 1 (Follow-Up Visits 1-3):  
 
- Negative Pregnancy Test Confirmed at Enrollment 
- Ovulation Testing  
- Positive Ovulation Test #1= Day 0 
- Study Followup Visits 1-3 Scheduled for days +7, +14, +22 
- Study Followup Visit 1 (Day +7): Assessments, administration of study agent patch A and 
dispensation of pills (Condition 1) 
- Study Followup Visit 2 (Day +14): Assessments, replacement of study agent patch A with 
patch B (Condition 1) 
- Removal of study patch and end of pills on day +21 
- Study Followup Visit 3 (Day +22): Assessments, Pregnancy Test 
 
Condition 2 (Follow-Up Visits 4-6):  
 
- Negative Pregnancy Test Confirmed at Visit 3 
- Ovulation Testing  


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- Positive Ovulation Test #2= Day 0 
- Study Followup Visits 4-6 Scheduled for days +7, +14, +22 
- Study Followup Visit 4 (Day +7): Assessments, administration of study agent patch A and 
dispensation of pills (Condition 2) 
- Study Followup Visit 5 (Day +14): Assessments, replacement of study agent patch A with 
patch B (Condition 2) 
- Removal of study patch and end of pills on day +21 
- Study Followup Visit 6 (Day +22): Assessments, Schedule Debriefing 
 
7.3.4 FINAL STUDY VISIT 
 
Debriefing visits will be scheduled within 15 days of study completion. In this final visit, a final 
risk assessment will be conducted and the participant will be referred as appropriate for 
additional clinical care. This final risk evaluation visit is included in order to reduce the likelihood 
of emergent risk following withdrawal from exogenous hormones in women who had the 
placebo-experimental condition order. Participants will not be provided with individualized study 
results.  
 
7.3.5 EARLY TERMINATION VISIT 
 
Should early termination be deemed necessary (following procedures detailed above), and the 
situation does not involve a need for immediate hospitalization of the participant, then the 
participant will be invited to an early termination visit in which the full typical debriefing interview 
(i.e., risk assessment and referral as appropriate) will be conducted.  
 
7.3.6 UNSCHEDULED VISIT 
 
There will be no unscheduled visits. Should a participant present at the laboratory at the wrong 
time, a member of the study staff will reschedule the visit if needed or refer her to her mental 
health provider as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.3.7 SCHEDULE OF EVENTS TABLE 
Procedures 
Screening 
Enrollment/Baseline 
IDS RANDOMIZATION 
Follow-Up (Condition 1, Visit 1) 
Follow-Up (Condition 1, Visit 2) 
Follow-Up (Condition 1, Visit 3) 
Follow-Up (Condition 2, Visit 4) 
Follow-Up (Condition 2, Visit 5) 
Follow-Up (Condition 2, Visit 6) 
Final Visit/ Debriefing Visit 
Informed Consent 
Verbal 
x 
Written 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
x 
 
 
 
 
 
 
 
 
Medical History/Inclusion/Exclusion Criteria 
x 
x 
 
 
 
 
 
 
 
 
SCID – Diagnostic Interview 
 
x 
 
 
 
 
 
 
 
 
SITBI – Suicidality Interview 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
Administer Study Agent E2 (or placebo) Patch 
 
 
 
x 
x 
 
x 
x 
 
 
Dispense Study Agent P4 (or placebo) Pills 
 
 
 
x 
x 
 
x 
x 
 
 
Height/Weight  
 
x 
 
 
 
 
 
 
 
 
E2/P4 Serum Measure 
 
 
 
x 
x 
x 
x 
x 
x 
 
CESD - Depression Self-Report 
 
 
 
x 
x 
x 
x 
x 
x 
 
BHI – Hopelessness Self-Report 
 
 
 
x 
x 
x 
x 
x 
x 
 
STAI – Anxiety/Threat Sensitivity Self-Report 
 
 
 
x 
x 
x 
x 
x 
x 
 
SSES – Negative Social Appraisals Self-Report 
 
 
 
x 
x 
x 
x 
x 
x 
 
UPPS-P – Impulsivity/Inhibitory Control Self-Report 
 
 
 
x 
x 
x 
x 
x 
x 
 
FT-IRAP – Hopelessness Task 
 
 
 
x 
x 
x 
x 
x 
x 
 
SAR-IAT – Negative Social Appraisal Task 
 
 
 
x 
x 
x 
x 
x 
x 
 
SST – Inhibitory Control Task 
 
 
 
x 
x 
x 
x 
x 
x 
 
DPT – Threat Sensitivity Task 
 
 
 
x 
x 
x 
x 
x 
x 
 
Adverse Event/Side Effect Evaluation 
 
 
 
x 
x 
x 
x 
x 
x 
 
 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
 
Placebo control is required to demonstrate unique effects (vs. expectancy effects) of hormones 
on indices of suicidality.  
 
Ongoing Assessment of Suicidality 
 
The PI (Dr. Eisenlohr-Moul) is a clinical psychologist with seven years of experience in risk 
assessment and empirically supported treatment of chronic suicidality (e.g., Dialectical Behavior 
Therapy); Dr. Prinstein, the consulting clinical psychologist, has over 20 years of experience in 
risk assessment and treatment of chronic suicidality. The PI and her mentors have also 
conducted several studies assessing depressive symptoms in women with borderline 
personality disorder or chronic suicidality, most of which included structured interviews for the 
assessment of suicidality and other psychiatric symptoms. The available literature3 indicates 
that participants in research studies do not generally become acutely upset in response 
to the psychological assessments conducted in the present study. If participants do 
become upset during an assessment, they will be reminded of their right to discontinue 
participation, and mood changes or suicidality will be assessed and managed using the 
University of Washington Risk Assessment and Management Procedure (UWRAP), the suicide 
risk management protocol recommended by NIH in the context of RCTs for mood disorders.  


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7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
 
All concomitant prescription medications taken during study participation will be recorded. For 
this protocol, a prescription medication is defined as a medication that can be prescribed only by 
a properly authorized/licensed clinician. Medications to be reported are concomitant prescription 
medications, over-the-counter medications and non-prescription medications. 
 
 
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
There are no medications that are prohibited for concomitant use with the study agents, with the 
exception of any hormonal preparations (that are exclusionary). 
 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
There are no prohibited medications or procedures except hormonal preparations, which are 
exclusionary. 
 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Not applicable. 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Not Applicable.  
 
Hospitalization will serve as a “rescue treatment” should imminent suicidal risk emerge. 
 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
 
Participants will not be provided access to study medications following the termination of this 
study; as noted above, this is a mechanistic experimental study and not a treatment study. 
 
8 
ASSESSMENT OF SAFETY 
 
The safety of the study and its participants (as described in 2.3.1) will be monitored via 
(1) Supervising clinicians David Rubinow, M.D. (hormone-related AEs) and Mitch 
Prinstein, Ph.D. (mood and suicide-related AEs) as well as (2) a Data and Safety 
Monitoring Board (DSMB).  
 
AEs will be assessed daily during the telephone contacts in the two administration 
conditions, and will be assessed weekly at laboratory visits. All AEs will be reported 
immediately to the PI and Dr. Girdler, who will determine severity and next steps in 
consultation with the appropriate clinical supervisor (Rubinow for physical adverse 
events, Prinstein for psychological and behavioral adverse events). 


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The DSMB will evaluate AEs that are submitted during scheduled reviews. The North 
Carolina Translational and Clinical Sciences (NCTraCS) Data and Safety Monitoring 
Board (NCTraCS DSMB) has agreed to serve in this role. The Board is composed of 
MDs from a variety of disciplines, an R.N. from the UNC School of Nursing, a 
Biostatistician, a Regulatory Expert, and for purposes of this study, a psychiatrist or 
clinical psychologist may serve as an ad hoc member.  
 
Although not expected given the doses and duration of hormone exposure, the DSMB 
will, during scheduled reviews, specifically evaluate the frequency of AEs related to the 
hormonal RCT. The DSMB will specify the tables and data it wishes to have presented 
to it at all meetings, including but not limited to, moderate to severe side effects and all 
serious adverse events. DSMB review of this study will occur every six months. At 
these meetings the DSMB will also review data from participants who have been 
discontinued by study staff or who have withdrawn or dropped out of the study, and the 
reasons for discontinuation. The DSMB will also identify if any study procedures should 
be altered or stopped in the event of an indication of harm to participants attributable to 
the study interventions. The DSMB will evaluate issues of participant safety as well as 
the adequacy and integrity of accumulating data, review of enrollment data, and making 
recommendations regarding safety. 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention inhumans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
Serious adverse event or serious suspected adverse reaction. An AE or suspected adverse 
reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization 
or prolongation of existing hospitalization, or a persistent or significant incapacity. Important 
medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical intervention to prevent one of the outcomes 
listed in this definition.  
 
*Notable examples of serious adverse events in the present study include development 
of a venous thromboembolism or suicide attempt.  
 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
OHRP considers unanticipated problems involving risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria:  


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• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied;  
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and  
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized.  
 
This study will use the OHRP definition of UP. 
 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
 
For AEs not included in the protocol defined grading system, the following guidelines will be 
used to describe severity. 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.  
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
 
 
 
 
8.2.2 RELATIONSHIP TO STUDY AGENT 
 
For all AEs, Drs. Girdler and Eisenlohr-Moul will urgently collaborate with appropriate clinical 
supervisors (Rubinow for physical/medical events, Prinstein for behavioral/psychological 
events) to determine the AE’s causality based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event occurs in a plausible time 
relationship to drug administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a 
satisfactory rechallenge procedure if necessary.  
Probably Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event occurs within a reasonable time after administration 
of the drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, and 


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follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information 
is not required to fulfill this definition.  
 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” 
or“definitely related,” as appropriate. 
 
Unlikely to be related – A clinical event whose temporal relationship to drug administration 
makes a causal relationship improbable (e.g., theevent did not occur within a reasonable time 
after administration of the trial medication) and inwhich other drugs or chemicals or underlying 
disease provides plausible explanations (e.g., theparticipant’s clinical condition, other 
concomitant treatments). 
 
Not Related – The AE is completely independent of study drug administration, and/or 
evidenceexists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by Dr. Rubinow or Dr. Prinstein. 
 
 
8.2.3 EXPECTEDNESS  
 
Drs. Girdler and Eisenlohr-Moul will collaborate with appropriate clinical supervisors (Rubinow 
for physical/medical, Prinstein for psychological/behavioral) to make determinations about 
whether an AE is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent. 
 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant. All AEs including local and systemic reactions not 
meeting the criteria for SAEs will be captured on the appropriate documentation. Information 
to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed 
to adequate resolution.  
 
Pre-existing medical conditions are exclusionary for participation in the trial, with the 
exception of psychiatric conditions. Any psychiatric condition or symptom that is present at 
the time that the participant is screened, including mood symptoms and suicidal ideation, will 
be considered as baseline and not reported as an AE. However, if the study participant’s 
condition or symptom deteriorates significantly with regard to the severity or impact of the 
symptom on the participants functioning or safety (as determined by Drs. Eisenlohr-Moul, 
Girdler, Rubinow, and Prinstein) at any time during the study, it will be recorded as an AE. 


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UPs will be recorded in the data collection system throughout the study.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.  
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation. At each phone call and study visit, study staff will inquire about the 
occurrence of AE/SAEs since the last visit. All AEs will be immediately (within 2 hours) reported 
to the PI, who will consult with Drs. Girdler, Rubinow, and Prinstein in the 24 hours that follow. 
Events will be followed for outcome information until resolution or stabilization. 
 
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
 
Study staff will screen for all AEs at each telephone call and study visit. Dr. Eisenlohr-
Moul or Dr. Prinstein will be on call for all visits and telephone calls to ensure that 
emergent mood deterioration or suicide risk can be immediately handled by a licensed 
clinical psychologist with experience in suicide risk assessment (Eisenlohr-Moul or 
Prinstein) using the LRAP/UWRAP protocol (the tool recommended by NIH for clinical 
trials with suicidal subjects). Medical/physical AEs will be discussed as soon as 
possible, and within the following 24 hours, with Drs. Girdler and Rubinow.  
 
The PI Dr. Eisenlohr-Moul (in consultation with Drs. Girdler, Rubinow, and Prinstein) will 
review all protocol data at weekly meetings, including enrollment and retention statistics 
and aggregate reports of side effects/AEs. As the contact PI, Dr. Eisenlohr-Moul will be 
the one responsible for reporting any severe AEs to the IRB and DSMB within 1 week. 
Since we are employing a marketed pharmaceutical product (i.e., a non-IND study), 
unexpected Serious AEs will be also be reported to the FDA Medwatch Program. The 
NIMH program officer will be notified of any study modifications or suspension imposed 
by the DSMB or local IRB in response to an AE. 
 
 
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
 
The PI (Dr. Eisenlohr-Moul) will complete a SAE Form within the following timelines:  
• 
All deaths and immediately life-threatening events, whether related or unrelated, will be 
recorded on the SAE Form and submitted to the DCC/study sponsor within 24 hours of 
site awareness. See Section 1, Key Roles for contact information.  
 
All SAEs will be followed until satisfactory resolution or until the PI deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be 
requested by the DSMB or study sponsor and will be provided as soon as possible. The study 
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suspected adverse reaction as soon as possible but in no case later than 7 calendar days after 
the sponsor's initial receipt of the information. 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion 
of an UP report form. It is the site investigator’s responsibility to report UPs to their IRB and 
to the study sponsor. The UP report will include the following information:  
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
projectnumber; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcomerepresents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:  
• 
All UPs will be reported to the IRB, the DSMB, and to the study sponsor within 1 week of 
the investigator becoming aware of the event. 
 
8.4.4 EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.4.5 REPORTING OF PREGNANCY  
 
Pregnancy will result in immediate withdrawal from the study and a breaking of the blind 
to Dr. Rubinow; Dr. Rubinow will oversee appropriate clinical care, including supervised 
hormonal discontinuation.  
 
8.5 
STUDY HALTING RULES  
 
At six month intervals, the study biostatistician (Dr. Xia) will test whether there are significant 
differences in the occurrence of moderate, severe, and serious AEs in the placebo vs. the 
experimental condition with alpha set at .05. These results will be provided to DSMB along with 
the summary report of enrollment.  
 
Administration of study agent will be halted when three serious AEs* determined to be “probably 
related” are observed. The PI will immediately notify the DSMB when this occurs. The DSMB 
will notify the study sponsor and investigators immediately when the third severe event is 
reported and enrollment screens will stop accepting new study participants. Dr. Xia will again 
perform an unblinded statistical analysis to further determine whether active study medication 
(E2/P4) is significantly related to greater risk of AEs relative to placebo. All requested 
documentation will be provided to the DSMB. The DSMB will convene an ad hoc meeting by 
teleconference or in writing as soon as possible. The DSMB will provide recommendations for 


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proceeding with the study to the PI and the NIH. The study sponsor will inform all appropriate 
regulatory agencies of the temporary halt and the disposition of the study. 
 
The DSMB will consider stopping the entire study based on the results of the statistical tests 
provided by Dr. Xia: specifically, if the experimental hormone stabilization condition is 
associated with greater risk of severe or serious AEs than placebo, and there is evidence (as 
determined by David Rubinow) that such AEs are causally related to the study drug, the study 
will be terminated.  
 
*Notable examples of serious adverse events in the present study include development 
of a venous thromboembolism or suicide attempt.  
 
 
8.6 
SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise as determined by their regulatory guidelines. The DSMB will meet every 6 
months to assess safety and efficacy data in each condition of the study. The DMSB will 
operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. The DSMB will provide its input as required to NIMH. 
 
9 
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s).  
• 
Katherine McCann, the project manager, will be responsible for the adequate clinical 
documentation of all events as described in the current protocol, including data 
verification and backup.  
• 
Evaluation of the safety of the study will take place via the DSMB every six months and 
as needed when AEs emerge (see sections above).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10 
STATISTICAL CONSIDERATIONS  
 
10.1 STATISTICAL AND ANALYTICAL PLANS 
 
There will be no formal SAP. The PI will conduct all analyses at the end of the trial.  
 
10.2 STATISTICAL HYPOTHESES 
 
Hypotheses. For suicidal desire 
and suicidal action capacity—our 
primary endpoints (see far right side 
of figure in Figure at right)—we 
predict that perimenstrual increases 
in suicidal desire and action capacity 
(Lab 2 – Lab 1 within each condition) 
will be larger in the placebo 
condition than in the experimental 
hormone stabilization condition. The 
associated null hypothesis is that 
there will be no difference in the 
perimenstrual increase in suicidality 
across condition. For our secondary 
endpoints, including hopelessness, 
negative social appraisals, reduced 
inhibitory 
control, 
and 
threat 
sensitivity, we predict the same 
pattern of results.   
 
There are no “efficacy” endpoints in the present trial since it is mechanistic and not a treatment 
study. 
 
10.3 ANALYSIS DATASETS 
 
An intent-to-treat dataset will be utilized. The study statistician will use a carry-forward approach 
to evaluate the within-person condition effect using this intent-to-treat sample.  
 
10.4 DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
 
The design of this study is a two-period crossover design, where each of two study 
periods is a perimenstrual frame of the menstrual cycle (days +7 to +22 following 
ovulation where positive ovulation test day=0). Each participant will complete both 
conditions in a randomized order.  
 


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The primary windows of comparison will be the final seven days of each administration 
phase, which will allow for a comparison of a woman’s mean scores in the placebo 
condition compared to her mean scores in the experimental condition. 
 
Primary hypothesis tests will be evaluated using a alpha level of .05, with a two-tailed 
test. 
 
All outcomes will be checked for normality; given the low likelihood that suicidality will 
follow a normal distribution even in this clinical sample, we expect that we will need to 
utilize nonparametric procedures.  
 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Primary and secondary endpoints are operationalized above (i.e., mean within-person 
differences between placebo and experimental in final seven days of manipulation) for 
the daily SITB suicidal ideation and planning subscales (primary endpoints) as well as 
the daily UPPS-P impulsivity, PROMIS anxiety, CESD depression, BHI hopelessness, 
and SSES rejection sensitivity subscales (secondary endpoints).  
 
Analyses will proceed identically for all outcomes listed above. First, we will 
calculate each subject’s mean daily rating (via phone) on the outcome measure in the 
final seven days of both the placebo condition (placebo mean score) and the 
experimental condition (experimental mean score).  
 
Second, we will utilize paired samples t-tests to examine the within-person condition 
effect. If proposed covariates (medicines, BMI, age) show sufficient variability, we will 
instead use a repeated measures ANCOVA to evaluate the condition effect. These 
analyses will be conducted on the intent-to-treat dataset. 
 
If necessary due to violations of model assumptions, we will utilize similar 
nonparametric tests. 
 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
See above.  
 
10.4.4 SAFETY ANALYSES 
 
All adverse events will be recorded once per condition for each subject, calculated 
dichotomously based on its emergence during the treatment timeframe. These 
outcomes will be presented in tables for review by the DSMB, and such outcomes will 
be accompanied by descriptive and inferential statistics (both mean levels and change 
from baseline in each condition) to determine whether AEs and changes in AEs are 
more likely to occur in the experimental condition.  
 
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and will therefore be monitored most closely (at every daily and weekly participant 
contact during administration of study agents). However, participants will have the 
opportunity to report any other adverse event in addition to those listed below. 
 
GENERAL ADVERSE EVENTS 
 
• 
Significant deterioration in mood  
• 
Significant deterioration in suicidality 
• 
Any adverse event related to venipuncture 
• 
Any adverse event related to emotional or behavioral reactions to interviews, 
questionnaires, or tasks 
 
ESTRADIOL PHYSICAL SIDE EFFECT ADVERSE EVENTS 
 
The most frequent side effects associated with estradiol use include: 
- breast tenderness (occurs in 29% of patients) 
- abdominal cramps (occurs in 16% of patients) 
- headache (occurs in 13% of patients) 
- edema (swelling) (occurs in 10% of patients) 
- nausea (occurs in 6% of patients) 
- acne (occurs in 3 – 12% of patients) 
- skin rash or irritation may also occur at site where the patch is placed (occurs in 3 - 12% of 
patients) 
 
Rare side effects (<1%) include: 
- jaundice (yellowing of skin) 
- increased blood pressure 
- worsening of migraines or asthma 
- enlargement of uterine fibroids 
- intolerance to contact lenses 
- dizziness 
- changes in appetite and weight 
 
PROGESTERONE PHYSICAL SIDE EFFECT ADVERSE EVENTS 
 
The most common side effects associated with progesterone include: 
- breast tenderness (occurs in 16% of patients) 
- dizziness (occurs in 24% of patients) 
- abdominal cramping (occurs in 20% of patients) 
- headache (occurs in 16% of patients) 
- viral infection (occurs in 12% of patients) 
- joint pain (occurs in 12% of patients) 
- diarrhea (occurs in 8% of patients) 
- menstrual bleeding, sometimes consistent with a heavy menstrual period (occurs in 
20-30% of 
patients) 
- drowsiness (occurs in 9% of patients) 
 
Rare (<1%) side effects include: 


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- vaginal discharge 
- chest pain 
- abdominal bloating 
 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
 
Adherence to hormone administration protocols will be characterized following the close 
of the study using serum assays for E2 and P4 during the active condition relative to 
hormonal profiles during the placebo condition; it will not be monitored in real time.  
 
Women will be monitored in their compliance daily during each study condition via a 
phone call with study staff. Any deterioration in adherence will be immediately remedied 
via increased reminders and phone calls. 
 
10.4.6  
BASELINE DESCRIPTIVE STATISTICS 
 
Groups (counterbalanced order as placebo-experimental or experimental-placebo) will 
be compared on demographic factors such as age, severity of perimenstrual mood 
change in the placebo condition, and general suicidality. However, inferential statistics 
are not necessary as our primary outcome modeling procedures will control for any 
baseline differences that exist.  
 
10.4.7 PLANNED INTERIM ANALYSES  
 
10.4.7.1 
SAFETY REVIEW 
 
At six month intervals, the study biostatistician (Dr. Xia) will test whether there are significant 
differences in the occurrence of moderate, severe, and serious AEs in the placebo vs. the 
experimental condition with alpha set at .05. These results will be provided to DSMB along with 
the summary report of enrollment.  
 
Administration of study agent will be halted when three serious AEs* determined to be “probably 
related” are observed. The PI will immediately notify the DSMB when this occurs. The DSMB 
will notify the study sponsor and investigators immediately when the third severe event is 
reported and enrollment screens will stop accepting new study participants. Dr. Xia will again 
perform an unblinded statistical analysis to further determine whether active study medication 
(E2/P4) is significantly related to greater risk of AEs relative to placebo. All requested 
documentation will be provided to the DSMB. The DSMB will convene an ad hoc meeting by 
teleconference or in writing as soon as possible. The DSMB will provide recommendations for 
proceeding with the study to the PI and the NIH. The study sponsor will inform all appropriate 
regulatory agencies of the temporary halt and the disposition of the study. 
 
The DSMB will consider stopping the entire study based on the results of the statistical tests 
provided by Dr. Xia: specifically, if the experimental hormone stabilization condition is 
associated with greater risk of severe or serious AEs than placebo, and there is evidence (as 
determined by follow up with David Rubinow using unblinded data provided by Dr. Xia) that 
such AEs are causally related to the study drug, the study will be terminated.  
 


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*Notable examples of serious adverse events in the present study include development 
of a venous thromboembolism or suicide attempt.  
 
10.4.7.2 
EFFICACY REVIEW 
 
There are no efficacy endpoints in the present study because this is not a treatment 
study and the intervention used is not expected to be an effective treatment for any 
condition. 
 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
 
The study is not powered to conduct sub-group analyses, and therefore they will not be 
performed. 
 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
 
N/A 
 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
 
Individual response data will be tabulated only if requested by the DSMB.  
 
10.4.11 
EXPLORATORY ANALYSES 
 
Not applicable. 
 
10.5 SAMPLE SIZE 
 
An unlimited number of women will be screened. 45 women will be enrolled in the study, 
with the goal of 30 women completing the study.  
 
Power analyses are described below; alpha is set at .05, power at 80%. The null 
hypothesis is no link between the study experimental condition and risk for suicidal 
ideation, intent, and planning; the alternate hypothesis is that hormone stabilization in 
the experimental condition will prevent flux in these suicide-related outcomes. Because 
no previous studies have examined the impact of experimental hormones on suicidality, 
we have conducted power analyses using existing effect sizes on related constructs 
(e.g., BPD features).  
 
Power Analysis. For the contrast testing the primary hypothesis, we will have power to detect a 
conventionally medium-sized effect of hormone withdrawal (r = .30; d = .60) at 80% power with 
just 17 participants165. The PI’s previous work in women with BPD suggests that attrition could be 
as high as 25% across two conditions; should attrition be this high, enrollment of 22 participants 
would be required for adequate power. However, to improve generalizability of our findings and 
to ensure 80% power to detect small-to-medium effect sizes (r = .20; d = .40), we aim to include 
30 completers (with 45 women randomized). This number is especially reasonable given the 


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much larger effects found in the candidate’s recent studies for the effect of natural ovarian steroid 
changes (average r = .58; d = 1.38) on daily symptoms of depression, rejection sensitivity, anxiety, 
and impulsivity40. 
 
10.6 MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
 
Individuals will be enrolled following phone screen and an enrollment visit as described above. 
Individuals will be randomized by IDS to one of two counterbalanced condition orders (placebo-
experimental or experimental-placebo) following enrollment visit if they meet study criteria and 
give informed consent. Masking and blinding will be handled by IDS according to standard 
procedures for double blinding, and will be fully double-blind. Randomization codes will be kept 
by IDS until the completion of the study, and will be shared only as needed for unblinding as 
needed for safety monitoring (described above).  
Blinding of Participants and Staff. All study staff performing assessments will remain blinded 
to condition. The natural within-woman variation in menstrual cycle length from one cycle to 
another will help maintain the participant blind.  Few women have regular 28 day cycles, and 
between-cycle variation up to 8 days is normal4. Demand characteristics regarding the impact of 
hormonal manipulation will be minimized by informing participants that women vary a great deal 
in their responses to hormones, and our current evidence does not allow us to predict for certain 
whether hormones have a positive, negative, or neutral effect on women’s symptoms (of note, 
this is scientifically accurate39). Finally, although it is possible that some women may become 
unblinded later in the extended hormone phase if they have extremely regular cycles, work by the 
mentoring team suggests that pharmacologic delay of menses does not influence the course of 
perimenstrual mood symptoms144. 
 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
 
At the conclusion of the study, each participant will be asked to guess which condition 
order they had. Blinding will be evaluated by determining whether the accuracy of these 
reports is greater than 50% (chance).  
 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
 
Breaking of blind will occur to Dr. Rubinow in the case of severe physical AEs (e.g., 
VTE) or hospitalization/suicide attempt, and Dr. Prinstein will also be unblinded if severe 
AEs are related to suicidality.  
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
All data collected in this study will be maintained on the UNC protected servers and in 
clinical binders kept under lock and key in Dr. Girdler’s locked laboratory.  
 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
 


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QC procedures will be implemented beginning with the data entry system and data QC checks 
that will be run on the database will be generated; this will be carried out by study project 
manager Katherine McCann. Any missing data or data anomalies will be communicated to the 
PI for clarification/resolution.  
Following written SOPs, the monitors will verify that the clinical trial is conducted and 
data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 ETHICAL STANDARD  
 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
CFR Part 56, and/or the ICH E6. 
 
13.2 INSTITUTIONAL REVIEW BOARD  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented 
 
13.3 INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The following consent materials are submitted with this 
protocol including the adult informed consent and the consent for storage of specimens. 
 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families. 


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Consent forms will be IRB-approved and the participant will be asked to read and review the 
document. The investigator will explain the research study to the participant and answer any 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights 
as research participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participants will have the opportunity to 
discuss the study with family or health care providers and think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by  
 emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY  
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any 
unauthorized third party. 
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB and Institutional regulations.  
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored on protected servers at UNC Chapel Hill. Identifying 
information will be linked to ID number only in one password-protected file. Individual 
participants and their research data will otherwise be identified by a unique study identification 
number. The study data entry and study management systems used by study staff will be 
secured and password protected. At the end of the study, all study databases will be de-
identified and archived on UNC Chapel Hill servers. 
 
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
obtained from the NIH. This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse 
to disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
researchers and institutions from being compelled to disclose information that would identify 
research participants, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to participants. 
 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES,SPECIMENS OR DATA 
 
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study participation.  
 
• 
Intended Use: Samples and data collected under this protocol may be used to study 
suicidality and psychiatric symptoms. No genetic testing will be performed.  
 
• 
Storage: Access to stored samples will be limited using locked access areas. Samples 
and data will be stored using codes assigned by the investigators. Data will be kept in 
password-protected computers. Only investigators will have access to the samples and 
data.  
 
• 
Tracking: Data will be tracked using password-protected files on the UNC server. 
Disposition at the completion of the study: All serum samples will be kept under locked 
access areas at UNC and on secure UNC servers. Study participants who request 
destruction of samples will be notified of compliance with such request and all supporting 
details will be maintained for tracking. 
 
 
 
 
 
13.5 FUTURE USE OF STORED SPECIMENS  
 
Data collected for this study will be analyzed and stored at Dr. Susan Girdler’s laboratory at 
UNC. After the study is completed, the de-identified, archived data will remain in Dr. Girdler’s 
laboratory, under the supervision of medical technician Joe Hodges, for use by other 
researchers including those outside of the study. Permission to retain samples in Dr. Girdler’s 
laboratory will be included in the informed consent.  
With the participant’s approval and as approved by local IR s, de-identified biological samples 
will be stored at the Dr. Girdler’s laboratory. These samples could be used for research into the 
causes of suicidality and other psychiatric symtpoms, and to improve treatment.  
 
During the conduct of the study, an individual participant can choose to withdraw consent 
to have biological specimens stored for future research. However, withdrawal of consent 
with regard to biosample storage will not be possible after the study is completed.  
The data and samples collected in this study will not be shared with other investigators. 
14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the staff at the site under the supervision of the PI. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 


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changes or corrections, cross out the original entry with a single line, and initial and date the 
change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE 
ORIGINAL.  
 
Copies of the electronic data will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the electronic data file 
derived from source documents should be consistent with the source documents or the 
discrepancies should be explained and captured in a progress note and maintained in the 
participant’s official electronic study record.  
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) 
and laboratory data will be entered into a local database on UNC servers. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
 
14.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 2 years following the end of the study. These 
documents will be retained for a longer period, however, if required by local regulations. No 
records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to 
be retained. 
 
14.3 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly. 
 
These practices are consistent with ICH E6:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 7 working days of identification of the protocol deviation. All significant deviations must be 
addressed in study source documents, reported to NIMH Program Official and DSMB. Protocol 
deviations must be sent to the local IRB per their guidelines. The PI/study staff is responsible for 
knowing and adhering to their IRB requirements.  
 
14.4 PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  


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The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human subjects to intervention or concurrent 
comparison or control groups to study the cause-and-effect relationship between a medical 
intervention and a health outcome. Medical interventions include drugs, surgical procedures, 
devices, behavioral treatments, process-of-care changes, and the like. Health outcomes include 
any biomedical or health-related measures obtained in patients or participants, including 
pharmacokinetic measures and adverse events. The ICMJE policy, and the Section 801 of the 
Food and Drug Administration Amendments Act of 2007, requires that all clinical trials be 
registered in a public trials registry, which is sponsored by the National Library of Medicine. 
Other biomedical journals are considering adopting similar policies. For interventional clinical 
trials performed under NIH IC grants and cooperative agreements, it is the grantee’s 
responsibility to register the trial in an acceptable registry, so the research results may be 
considered for publication in ICMJE member journals. The ICMJE does not review specific 
studies to determine whether registration is necessary; instead, the committee  
recommends that researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish.  
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal 
investigator) register and report results of certain "applicable clinical trials":  
• 
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation; 
 
The PI will take specific steps to ensure compliance with NIH implementation of FDAAA. 
 
15 
STUDY ADMINISTRATION 
 
15.1 STUDY LEADERSHIP 
 
The PI and her key mentors (Girdler, Prinstein, Rubinow, Young) will govern the conduct of the 
study, along with NIMH program officer Mark Chavez. The PI will meet weekly with key mentors 
weekly as described in the NIMH K99 Career Development award on which this protocol is 
based. 
 
16 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the trial. The 
study leadership in conjunction with the NIMH has established policies and procedures for all 
study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
17  
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1. 
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APPENDIX 
 
Version 
Date 
Significant Revisions