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Facilitation of Extinction Retention and Reconsolidation Blockade in PTSD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04468360
Recruitment Status : Recruiting
First Posted : July 13, 2020
Last Update Posted : May 27, 2022
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Boston University

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):

  1. promotes consolidation of extinction learning (sub-study 1) or
  2. blocks reconsolidation physiological responses triggered by aversive memories (sub-study 2).

The study also tests whether Allo compared to placebo affects retention of non-aversive memories.


Condition or disease Intervention/treatment Phase
Post Traumatic Stress Disorder Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm Drug: Allopregnanolone (Allo) with Dexolve in 0.9% saline for injection manufactured by University of California, Davis Other: Matching IV Placebo Phase 2

Detailed Description:

Background: Allo is a neurosteroid (hormone) produced from progesterone by the brain, adrenal glands, testes, and ovaries. Production of Allo and its equally powerful, structurally similar, stereoisomer pregnanolone (PA) is stimulated when certain neurons in the brain are activated and when stress activates the adrenal glands. Allo and PA markedly increase effects of gamma-amino-butyric acid (GABA; an inhibitory neurotransmitter) in the brain, thereby regulating arousal and responses to stress. Allo and PA also influence processes that strengthen or weaken memories.

Basic research suggests that several factors can reduce production of Allo: exposure to chronic or extreme stress, prolonged social isolation, chronic intermittent heavy alcohol use, certain oral contraceptives, chronic use of some psychiatric medications or other substances used to manage PTSD such as nicotine, exposure to environment toxins, and genetic predisposition.

Research shows that Allo and PA production is reduced in a large subpopulation of women and men with PTSD. Reduced Allo and PA is strongly associated with severity and poor retention of extinction learning-both of which contribute to chronic PTSD. The proposed study thus will be conducted in adult men and women with chronic PTSD. Women will be studied during two distinct phases of the menstrual cycle because progesterone levels (and therefore levels of Allo and PA) change markedly across the menstrual cycle, as do problems with extinction retention.

Study Procedures: Eligible participants will take part in a widely used, standardized 3-day laboratory psychophysiology paradigm during which activation of the sympathetic nervous system (fight/flight system) is monitored via small electrode patches placed on the skin. The paradigm involves startle testing on Days 1, 2 and 3. During startle testing, participants will hear sudden bursts of white noise through headphones, see colored shapes on a computer screen, and feel sudden (not painful) blasts of air to the neck. The electrodes record participants' eye blinks, skin conductance, and heart rate. The startling sounds will be about as loud as a train but last only a fraction of a second. Participants will sit quietly with their eyes open as they listen. On study Day 2, participants are randomized by "luck of the draw" or chance to receive either IV Allo or placebo. On study Days 2 and 3, a brief memory test also will be conducted. Blood is collected each day for measurement of Allo, PA and other neurobiological factors that may affect the potential beneficial effects of Allo.

Before starting the above studies, the investigators will conduct pharmacokinetic (PK) studies in a small group of individuals with PTSD to confirm that the selected IV Allo dose increases blood Allo levels as expected.

Implications: These studies may help us understand treatable factors that increase risk for chronic or treatment-resistant PTSD and PTSD-related depression. They may also tell us whether treatments that increase Allo might help prevent or treat PTSD. IV Allo (at much higher doses than used in this study) is currently FDA-approved for treatment of postpartum depression-supporting the potential for this research to spur development of Allo as a new PTSD treatment.

Study Population 256 individuals with PTSD (about 85 males and 170 females) will be recruited to participate in these studies. Half of the women will be studied during the follicular phase of the menstrual cycle (after onset of menses) and half during the luteal phase (after ovulation). The study is being conducted at Boston University School of Medicine in Boston, Massachusetts, and half at Wayne State University School of Medicine in Detroit, Michigan.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 256 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Basic Science
Official Title: Facilitation of Extinction Retention and Reconsolidation Blockade by IV Allopregnanolone in PTSD
Actual Study Start Date : March 4, 2022
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1)
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: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm
Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.

Drug: Allopregnanolone (Allo) with Dexolve in 0.9% saline for injection manufactured by University of California, Davis
Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of Allo will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at ~1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of Allo will be infused over 30 minutes immediately following presentation of a single CS+.
Other Name: U.S. P. equivalent: brexanolone (SAGE Therapeutics) (IV Allopregnanolone with Captisol)

Placebo Comparator: IV Placebo for Extinction Retention (Expt. 1)
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: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm
Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.

Other: Matching IV Placebo
Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of the matching placebo formulation will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at ~1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of the matching placebo formulation will be infused over 30 minutes immediately following presentation of a single CS+.

Experimental: IV Allo for Reconsolidation Blockade (Expt. 2)
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 fear memory by exposure to one conditioned stimulus (CS+).
Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm
Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.

Drug: Allopregnanolone (Allo) with Dexolve in 0.9% saline for injection manufactured by University of California, Davis
Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of Allo will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at ~1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of Allo will be infused over 30 minutes immediately following presentation of a single CS+.
Other Name: U.S. P. equivalent: brexanolone (SAGE Therapeutics) (IV Allopregnanolone with Captisol)

Placebo Comparator: IV Placebo for Reconsolidation Blockade (Expt. 2)
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 fear memory by exposure to one conditioned stimulus (CS+).
Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm
Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.

Other: Matching IV Placebo
Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of the matching placebo formulation will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at ~1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of the matching placebo formulation will be infused over 30 minutes immediately following presentation of a single CS+.




Primary Outcome Measures :
  1. Extinction retention in Expt. 1 [ Time Frame: Day 3 ]
    To assess extinction retention the difference between the average skin conductance response (SCR) to the first 5 conditioned stimulus (CS+) trials and the average SCR to the first 5 CS- trials on Day 3 will be calculated. Extinction retention for SCR will be defined as this differential SCR minus the differential SCR for Day 2 (calculated as the difference between the average SCR to the last 5 CS+ trials and the average SCR for last 5 CS- trials-the index of Day 2 extinction). For fear-potentiated startle (FPS), the degree of FPS to the CS+ during the first 5 CS+ trials on Day 3 will be examined and compared to the FPS for the last 5 CS+ trials during extinction. Lower scores indicate better extinction retention.

  2. Reconsolidation blockade in Expt. 2 [ Time Frame: Day 3 ]
    Reconsolidation blockade on Day 3 will be calculated by a) examining the average FPS to the first two CS+ trials, and b) comparing the difference between the average SCR to the first two CS+ trials minus the average SCR to the first two CS- trials. Lower scores indicate better reconsolidation blockade.


Secondary Outcome Measures :
  1. Fear acquisition in Expt. 1 [ Time Frame: Day 1 ]
    Fear acquisition will be defined as the difference between the average SCR to the last two CS+ and the average SCR to the last two CS- trials during the acquisition phase (i.e., the differential SCR). For FPS, the last two trials of acquisition for each CS will be examined. (Because FPS is calculated as the difference between startle to the CSs compared to the noise alone (NA) trials, the standard is to use FPS to CS+ trials as the dependent variable (DV) rather than the difference between FPS to CS+ vs. CS- as is typically done for SCR). Higher scores indicate greater conditioned fear acquisition.

  2. Fear acquisition in Expt. 2 [ Time Frame: Day 1 ]
    Fear acquisition will be defined as the difference between the average SCR to the last two CS+ and the average SCR to the last two CS- trials during the acquisition phase (i.e., the differential SCR). For FPS, the last two trials of acquisition for each CS will be examined (Because FPS is calculated as the difference between startle to the CSs compared to the NA trials, the standard is to use FPS to CS+ trials as the DV rather than the difference between FPS to CS+ vs. CS- as is typically done for SCR). Higher scores indicate greater conditioned fear acquisition.

  3. Reinstatement of Conditioned Fear in Expt. 1 [ Time Frame: Day 3 ]
    Reinstatement of conditioned fear will be defined as the average SCR to the last five CS+ trials minus the average SCR to the last 5 CS- trials. For FPS, the last 5 CS+ trials will be examined. Higher scores indicate greater reinstatement of conditioned fear.

  4. Reinstatement of Conditioned Fear in Expt. 2 [ Time Frame: Day 3 ]
    Reinstatement of conditioned fear will be defined as the average SCR to the last five CS+ trials minus the average SCR to the last 5 CS- trials. For FPS, the last 5 CS+ trials will be examined. Higher scores indicate greater reinstatement of conditioned fear.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Posttraumatic Stress Disorder

Exclusion Criteria:

  • Bipolar I disorder, schizophreniform disorder, or substance use disorder within 3 months of study entry
  • History of a suicide attempt within 1 year of enrolling
  • Imminent risk to self or others or require clinical intervention to maintain safety
  • Unstable medical condition or condition that may affect outcomes
  • Moderate or severe traumatic brain injury (TBI) (mild TBI acceptable)
  • Using any medications or substances (by self-report or toxicology testing) that may increase the risk of the side effects of IV Allo or affect the experimental results.
  • Females: pregnant, breastfeeding, or if of childbearing potential, unwilling to use two forms of effective birth control for one week before and one month after study drug administration
  • Wear hearing aids or fail hearing test (not applicable to PK study)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04468360


Contacts
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Contact: Ann M Rasmusson, MD 617-358-1871 amrasmus@bu.edu
Contact: Kayla Brown kdb123@bu.edu

Locations
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United States, Massachusetts
Boston University School of Medicine Recruiting
Boston, Massachusetts, United States, 02118
Contact: Ann M Rasmusson, MD    617-358-1871    amrasmus@bu.edu   
Contact: Kayla Brown, MS, MS    617-358-1871    kdb123@bu.edu   
Sub-Investigator: Suzanne Pineles, PhD         
Sub-Investigator: Jennifer Fonda, PhD         
Sub-Investigator: Mieke Verfaellie, PhD         
United States, Michigan
Wayne State University Not yet recruiting
Detroit, Michigan, United States, 48202
Contact: Tanja Jovanovic, PhD    313-577-9247    tjovanovic@med.wayne.edu   
Contact: William Davie, BS    313-355-3097    daviewil@wayne.edu   
Sub-Investigator: Christine Rabinak, PhD         
Sub-Investigator: Seth Norrholm, PhD         
Sponsors and Collaborators
Boston University
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Ann M Rasmusson, MD Boston University School of Medicine, Dept of Psychiatry
Publications:

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Responsible Party: Boston University
ClinicalTrials.gov Identifier: NCT04468360    
Other Study ID Numbers: H-40643
R01MH122867 ( U.S. NIH Grant/Contract )
First Posted: July 13, 2020    Key Record Dates
Last Update Posted: May 27, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Boston University:
Extinction retention
Reconsolidation blockade
Fear conditioning paradigm
Conditioned threat stimulus (CS+)
Allopregnanolone (Allo)
Refractory PTSD
Trauma-focused therapy
Additional relevant MeSH terms:
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Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Trauma and Stressor Related Disorders
Mental Disorders
Pregnanolone
Brexanolone
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Neurosteroids
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
GABA Modulators
GABA Agents