Facilitation of Extinction Retention and Reconsolidation Blockade by IV Allopregnanolone in PTSD.

NCT07079761 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 20250006937R01MH122867-05
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose: About 6.4% of the U.S. population suffers from posttraumatic stress disorder (PTSD). Trauma-focused psychotherapies are generally effective in PTSD, but responses vary greatly across individuals and PTSD subpopulations. Neurobiological factors impacted by life experiences, stress, and genetics can affect treatment responses. These factors can alter brain capacities needed to reprocess traumatic memories prevent them from triggering intensely distressing, disruptive, out-of-place responses. For example, during psychotherapy for PTSD, trauma memory activation engages two competing brain processes that affect recovery: "extinction" versus "reconsolidation" of trauma-related emotional, physiological, and behavioral responses. This study tests whether a single intravenous (IV) dose of allopregnanolone (Allo) compared to placebo (which is non-active): promotes consolidation of extinction learning (sub-study 1) or blocks reconsolidation of physiological responses triggered by aversive memories (sub-study 2). The study also tests whether Allo compared to placebo affects retention of non-aversive memories.

Conditions

Post Traumatic Stress Disorder

Keywords

Trauma; Allopregnanolone; Neurosteroid

Outcome Measures

Primary Outcomes (2)

• Experiment 1: Extinction retention

  Extinction retention is calculated as a) the difference between the average skin conductance response (SCR) to the first 4 aversively conditioned stimulus (CS+) trials and the average SCR to first 4 neutral conditioned stimulus (CS-) trials on Day 3 minus b) the difference between the average SCR to the last 4 CS+ trials and last 4 CS- trials on Day 2.

  Day 3

• Experiment 2: Reconsolidation blockade

  Reconsolidation blockade will be assessed by calculating the average fear potentiated startle (FPS) response to the first 4 CS+ trials on Day 3. Lower scores indicate better reconsolidation blockade.

  Day 3

Secondary Outcomes (4)

• Experiment 1: Reinstatement of conditioned fear

  Day 3

• Experiment 2: Reinstatement of conditioned fear

  Day 3

• Reinstatement of Conditioned Fear in Expt. 1

  Day 3

• Reinstatement of Conditioned Fear in Expt. 2

  Day 3

Study Arms (4)

IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1)

EXPERIMENTAL

Arm 1 of Expt. 1 includes women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV Allo immediately after completion of extinction training.

Behavioral: Experiment 1: Three-day aversive conditioning, extinction, and extinction retention testing paradigm; Drug: Allopregnanolone (Allo) with 6% USP Dexolve (sulfobutyl ether-beta-cyclodextrin sodium salt) in 0.9% saline for IV infusion will be provided by the University of California, Davis, GMP manufacturer.

IV Placebo for Extinction Retention (Expt. 1)

PLACEBO COMPARATOR

Arm 2 of Expt. 1 includes women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV placebo immediately after completion of extinction training.

Behavioral: Experiment 1. Three-day aversive conditioning, extinction, and extinction retention testing paradigm; Other: Matching IV Placebo

IV Allo for Reconsolidation Blockade (Expt. 2)

EXPERIMENTAL

Arm 1 of Expt. 2 will include women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV Allo immediately after reactivation of the conditioned aversive memory by exposure to one conditioned stimulus (CS+).

Behavioral: Experiment 2. Three-day aversive conditioning, reconsolidation blockade, and testing paradigm; Drug: Allopregnanolone (Allo) with 6% USP Dexolve (sulfobutyl ether-beta-cyclodextrin sodium salt) in 0.9% saline for IV infusion will be provided by the University of California, Davis, GMP manufacturer.

IV Placebo for Reconsolidation Blockade (Expt. 2)

PLACEBO COMPARATOR

Arm 2 of Expt. 2 will include will include women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV placebo immediately after reactivation of the conditioned aversive memory by exposure to one conditioned stimulus (CS+).

Behavioral: Experiment 2. Three-day aversive conditioning, reconsolidation blockade, and testing paradigm; Other: Matching IV Placebo

Interventions

Experiment 1. Three-day aversive conditioning, extinction, and extinction retention testing paradigm BEHAVIORAL

Day 1: Aversive conditioning will involve the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a colored shape appearing on a computer monitor (conditioned stimulus). An auditory stimulus will serve as the startle probe. Day 2: Extinction training will occur followed by IV Allo administration. Day 3: The effects of IV Allo (administered on Day 2) on extinction retention as well as reinstatement of conditioned psychophysiological reactions will be assessed.

IV Placebo for Extinction Retention (Expt. 1)

Allopregnanolone (Allo) with 6% USP Dexolve (sulfobutyl ether-beta-cyclodextrin sodium salt) in 0.9% saline for IV infusion will be provided by the University of California, Davis, GMP manufacturer. DRUG

On Day 2 of Experiment 1, a 1.7 mcg/kg dose of IV Allo will be administered over 5 minutes at the completion of extinction training to raise resting plasma Allo plus pregnanolone (PA) levels by 1500 pg/ml. This will be followed by a 4-5-hour continuous infusion of IV Allo at 2.6 mcg/kg/hr to maintain resting plasma Allo levels at the target level.

Also known as: U.S. P. equivalent: brexanolone (SAGE Therapeutics) (IV Allopregnanolone with Captisol)

IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1)

Matching IV Placebo OTHER

On Day 2 of Experiment 1, participants randomized to placebo will receive IV matching placebo over 5 minutes at the completion of extinction training followed by a continuous infusion of matching placebo over the next 4-5 hours. The matching IV placebo will be administered according to the same per kg dosing regimen as that for active drug.

Also known as: 6% USP Dexolve alone in 0.9% saline for IV infusion will be provided by the University of California, Davis, GMP manufacturer.

IV Placebo for Extinction Retention (Expt. 1)

Experiment 2. Three-day aversive conditioning, reconsolidation blockade, and testing paradigm BEHAVIORAL

Day 1: Aversive conditioning will involve the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a colored shape appearing on a computer monitor (conditioned stimulus). An auditory stimulus will serve as the startle probe. Day 2: Brief exposure to the conditioned stimulus will be followed by IV Allo administration. Day 3: The effects of IV Allo (administered on Day 2) on reconsolidation blockade and reinstatement of conditioned psychophysiological reactions will be assessed.

IV Allo for Reconsolidation Blockade (Expt. 2)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between the ages of 18 and 55 (at time of enrollment), reproductively mature, and English speaking.
• Meet criteria for chronic PTSD (i.e., CAPS-5 determined PTSD duration more than 3 months).
• Generally healthy and not on any prohibited medications (that could affect study outcomes).
• Willing to abstain from alcohol for 2 weeks and from nicotine, marijuana or illicit drugs for 4 weeks before experimental procedures and throughout the study.
• For biological females:
• Natural menstrual cycle.
• If of childbearing potential, female and partner must use 2 types of effective birth control (except for hormonal contraceptives, unless IUD or a device like Nuvaring) for a week before the IV Allo or placebo infusion, and for one month after.

You may not qualify if:

• Present an imminent risk to self or others or require clinical intervention to maintain safety
• Diagnosis of moderate or severe substance use disorder within three months of screening per administration of the DIAMOND substance abuse evaluation. Diagnosis of a mild substance use disorder within three months of screening will be allowed if the participant agrees to abstain from illicit drugs for one month and/or alcohol for 2 weeks prior to the experimental procedures, has a negative screening or follow-up urine toxicology and/or saliva alcohol test (if the screening test is positive), and tests negative for these substances on the morning of the experimental procedures.
• Bipolar I disorder, schizophreniform disorders, or clinically significant psychotic symptoms apart from the presence of trauma-related sensory hallucinations or negative beliefs.
• History of a suicide attempt within 1 year of enrolling.
• Diagnosis of sleep apnea
• Awake resting O2 saturation \< 96%
• Severe renal failure with an eGFR \<30 ml/min
• During screening for eligibility:
• On the mornings of the PK-1, PK-2, Expt. 1 or Expt. 2 experimental procedures:
• Pregnancy (urine pregnancy tests given at each in-person session).
• Breast-feeding.
• Unable to tolerate IV placement or blood drawing by needle stick.
• Wear hearing aid(s) (For Expt. 1 and 2, not PK studies).
• Fail hearing test (For Expt. 1 and 2, not PK studies).

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Wounds and Injuries

Interventions

Pregnanolone; SBE7-beta-cyclodextrin; Sodium Chloride; SBE4-beta-cyclodextrin

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Central Study Contacts

Kristen Curran

CONTACT

(617) 726-8508; kcurran0@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: In this double-blind, placebo controlled, randomized trial, active drug and matching placebo will be supplied by the research pharmacy. Participants, assessors, and the investigators will be blind to treatment condition.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigar

Model Details: Active drug vs. placebo will be administered in two separate experiments to a population of medically healthy, non-medicated patients with PTSD stratified by sex and by menstrual phase within female sex.

Study Record Dates

• First Submitted: June 3, 2025
• First Posted: July 23, 2025
• Study Start: August 4, 2025
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2027
• Last Updated: November 5, 2025

Record last verified: 2025-07

Locations

US (1)