Estrogen and Fear in PTSD

• ClinicalTrials.gov Identifier: NCT04192266
• Recruitment Status: Recruiting
• First Posted: December 10, 2019
• Last Update Posted: February 1, 2023
• Sponsor: NYU Langone Health
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief Summary:

The purpose of this research study is to determine if taking a pill of estradiol (E2) together with prolonged exposure (PE) therapy can improve this treatment outcome in women diagnosed with Post-Traumatic Stress Disorder (PTSD). 80 subjects will take part in this research study across NYU Langone Health and UPenn (40 subjects at each site). Participants will be randomized into one of two groups, PE + E2 or PE + placebo. The study will include preliminary screening and baseline visits, experimental visits, and therapy visits over the course of six weeks. Several follow-up visits will take place.

Condition or disease	Intervention/treatment	Phase
PTSD	Drug: Estradiol; Drug: Placebo oral tablet	Phase 3

Detailed Description:

Prolonged-exposure (PE) therapy is the treatment of choice for posttraumatic stress disorder (PTSD). Despite its efficacy, a significant number of individuals will not benefit from it or might drop out before the completion of all sessions. This underlies the importance of findings ways to enhance the efficacy of PE in order to improve the life quality of individuals suffering from PTSD. It is now widely accepted that extinction learning paradigms used in fundamental studies are useful laboratory analogs to PE. Studies in healthy controls have suggested that elevated estrogen levels benefit extinction learning by promoting its consolidation and thus enhancing its recall when tested later for it. This is also being reflected by changes in the activation of brain regions forming the fear extinction network, including the amygdala, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC). It is still unknown whether estradiol (E2) administration can modulate the activation of the fear extinction network in oral contraceptive (OC) users and which E2 dose could yield the best results. During the R61 phase of the study, we found that both doses of E2 were effective in engaging the functional activation of the fear extinction network. Therefore, we will use the lower dose (2mg) for the R33 phase. We will combine E2 administration with PE sessions to see if administration of PE can significantly improve clinical outcomes (reduced PTSD symptoms) and engage the fear extinction network in the brain.

Hypothesis: A general improvement is expected after 3 weeks of treatment in both groups given the anticipated benefits of PE alone. But the benefit of the Estradiol-treated groups is hypothesized be larger; with this group exhibiting significantly higher activation in brain regions associated with fear extinction. This will be noted at the follow-up scan compared to the baseline scan.

PTSD symptom severity expected be significantly lower in the Estradiol and PE group relative to the Placebo+PE group following acute treatment after three weeks of treatment.

The degree of PTSD symptom reduction post- compared to pre-PE after 3 weeks of treatment is expected be associated with BOLD changes in the fear extinction network and reduction in SCR during the extinction recall test after PE. The magnitude of BOLD and SCR changes will be significantly larger in the E2+PE group compared to the Plc+PE group.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Masking Description: double blinded
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind Placebo-controlled Multi-center Study of Identifying Neural Mechanisms of PTSD Symptom Reduction Induced by Combined Estrogen and Prolonged Exposure Therapy
• Actual Study Start Date: June 24, 2020
• Estimated Primary Completion Date: July 31, 2024
• Estimated Study Completion Date: July 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Prolonged Exposure (PE) therapy with estradiol; A 2.0 mg pill of estradiol (a form of estrogen) together with prolonged exposure (PE) therapy can improve this treatment outcome in women diagnosed with Post-Traumatic Stress Disorder (PTSD). Prolonged Exposure (PE) therapy is a validated treatment for PTSD. A single dose of estradiol 2mg or placebo will be taken at home by the study participant 5-6 hours before each of 5 PE treatment sessions (sessions 2 to 6)	Drug: Estradiol; 2.0 mg of estradiol will be taken by mouth by the study participant 5-6 hours before each of 5 PE treatment sessions (Session 2- 6); Other Name: Estrace
Placebo Comparator: Prolonged Exposure (PE) therapy with placebo; A 2.0 mg placebo pill will be given with prolonged exposure (PE) therapy can improve this treatment outcome in women diagnosed with Post-Traumatic Stress Disorder (PTSD). Prolonged Exposure (PE) therapy is a validated treatment for PTSD.	Drug: Placebo oral tablet; 2.0 mg placebo pills will be taken by mouth by the study participant 5-6 hours before each of 5 PE treatment sessions ( Sessions 2-6)

Outcome Measures

Primary Outcome Measures :

1. Change from Baseline on extinction-induced functional MRI responses. [ Time Frame: Visit 1-3 (Day 1-3) ]
   The outcome measure is brain activation within fear extinction network.

Secondary Outcome Measures :

1. Change from Baseline on PTSD symptom severity [ Time Frame: Visit 13 -15 (1, 3, and 6 months follow up) ]
   The outcome measure is change in PTSD severity as indexed by CAPS scores.
2. Changes from Baseline in PTSD symptoms correlations with Bold and SCR changes [ Time Frame: Visit 1-3 (Day 1-3) ]
   The degree of PTSD symptom reduction post- compared to pre-PE after 3 weeks of treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Estrogens are female sex hormones that are primarily produced by the ovaries and include estrone (E1), estradiol (E2) and estriol (E3). E2 is the predominant and most potent circulating estrogen produced during the reproductive years in non-pregnant women and is commonly prescribed in pill and transdermal form to treat postmenopausal symptoms
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Female, 18-45 years of age
2. Chronic (at least one month post-trauma) DSM-5 PTSD symptoms
3. CAPS-5 Past Month score ≥ 26
4. Criterion A traumatic event
5. Stable medications for 3 or more months by the time of study entrance (with the exception of benzodiazepines)
6. Women on oral contraceptives, specifically those using monophasic or biphasic of first, second, third or fourth generation with up to 35mcg of ethinyl estradiol; OR using etonogestrel / ethinyl estradiol 0.120mg/0.015mg per day vaginal ring (NuvaRing) birth control; OR using the norelgestromin / ethinyl estradiol 0.150mg/0.035mg per day transdermal patch birth control.
7. Willing and able to provide informed consent

Exclusion Criteria:

1. Diagnosis of bipolar I disorder with a past year manic episode
2. Diagnosis of a psychotic disorder or psychotic symptoms that would interfere with the ability to focus on posttraumatic stress disorder (PTSD) in clinic, as determined by clinical judgment.
3. Diagnosis of moderate or severe substance use disorder that would interfere with the ability to focus on posttraumatic stress disorder (PTSD) in clinic, as determined by clinical judgment.
4. Cognitive impairment that would interfere with the ability to focus on posttraumatic stress disorder (PTSD) in clinic, as determined by clinical judgment.
5. History of neurological disease (that involves the brain), seizure, or significant head trauma (i.e., extended loss of consciousness, neurological sequelae, or known structural brain lesion).
6. Suicidal ideation with imminent risk that warrants a higher level of care.
7. Concurrent trauma focused psychotherapy
8. Pregnancy (to be ruled out by urine ß-HCG).
9. Metallic implants or devices contraindicating magnetic resonance imaging by interfering with patient safety or fMRI data collection. Cases will be cleared by the Principal Investigator and Center for Brain Imaging
10. History of breast cancer or hormone-responsive cancer.
11. Use of benzodiazepines
12. Self-injurious behavior that involves suicidal intent, requires medical attention, or occurs daily.

Contacts and Locations

Contacts

Contact: Mohammed R Milad, PhD; 646-754-7046; Mohammed.milad@nyulangone.org

Locations

United States, Pennsylvania

University of Pennsylvania Perelman School of Medicine; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Edna Foa, PhD 215-746-3327 foa@pennmedicine.upenn.edu

Sponsors and Collaborators

NYU Langone Health

Investigators

• Principal Investigator: Mohammed R Milad, PhD; NYU Langone Health

More Information

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT04192266
• Obsolete Identifiers: NCT03371654
• Other Study ID Numbers: 19-01051
• First Posted: December 10, 2019
• Last Update Posted: February 1, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

Access Criteria

The investigator who proposed to use the data will have access and will provide upon reasonable request.

Requests should be directed to Mohammed.milad@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Estradiol; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs