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

Mass General Brigham

Status and phase: Enrolling; Phase 2

Conditions: Post Traumatic Stress Disorder

Treatments: 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.; Behavioral: Experiment 2. Three-day aversive conditioning, reconsolidation blockade, and testing paradigm; Other: Matching IV Placebo; Behavioral: Experiment 1: Three-day aversive conditioning, extinction, and extinction retention testing paradigm; Behavioral: Experiment 1. Three-day aversive conditioning, extinction, and extinction retention testing paradigm

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT07079761

7R01MH122867-05 (U.S. NIH Grant/Contract)

2025000693

Details and patient eligibility

About

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.

Full description

Background: Allo is a neurosteroid (hormone) produced from progesterone by the brain, adrenal glands, testes, and ovaries. Production of Allo and its equally potent, 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 PTSD 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 between 18 and 55 years of age 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. There will be a follow up phone session (about a week after the Day 3 visit/session).

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 doses increase 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 (brexanolone) at much higher doses than used in this study) is currently FDA-approved for the treatment of postpartum depression, supporting the potential for this research to spur development of Allo as a new treatment for PTSD.

Study Population: About 96 individuals with PTSD (between 18-55 years of age) 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 Massachusetts General Hospital, Boston, MA.

Enrollment: 96 estimated patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• 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.

Exclusion criteria

• 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.

• A history of severe TBI is exclusionary for the PK-1 and PK-2 studies. A history of moderate or severe TBI is exclusionary for the main studies (i.e., Expt. 1 and Expt. 2).

• Diagnosis of sleep apnea

• Awake resting O2 saturation < 96%

• Severe renal failure with an eGFR <30 ml/min

• Use of medications or substances (by report or toxicology testing) will be exclusionary under the following conditions:

  1. During screening for eligibility:

     1. Use of illicit substances, as well as prescribed opiates or benzodiazepines (either reported or detected on urine toxicology testing) will be exclusionary.
     2. Reported non-dependent use of cannabinoids or nicotine (indicated by a positive urine toxicology or cotinine test at screening) will not be exclusionary if the individual agrees to abstain from cannabinoids and nicotine for one month prior to the experimental procedures, has a follow-up negative screening test, and tests negative for these substances on the mornings of experimental procedures.
     3. A positive urine alcohol test at medical screening (which indicates uncontrolled alcohol use and likely moderate to severe alcohol dependence) will be exclusionary.
     4. A high serum gamma-glutamyl-transferase (GGT) test at screening (indicative of more remote recent drinking but not necessarily moderate to severe alcohol use or dependence) will not be exclusionary if the individual does not meet criteria for a moderate or severe alcohol use disorder within three months of screening, agrees to abstain from drinking for 2 weeks prior to the experimental procedures, and has normal follow-up urine alcohol and serum GGT tests.
     5. Use of non-illicit over the counter or prescribed medications that may increase the risk of IV Allo side effects or adversely affect the experimental results is exclusionary. Participants may agree to stop non-psychotropic medications used on a prn basis, such as acetaminophen, ibuprofen, or loratadine (a CYP3A inhibitor) for 5 half-lives of the parent drug or active metabolite (whichever is longer) before the experimental procedures. Regular psychotropic medications (including those used to treat non-psychiatric conditions, such as alpha1-antagonists prescribed for hypertension or urinary hesitancy) may be discontinued under the management of the potential participant's non-study prescriber for 3 months before evaluation for eligibility and participation in subsequent experimental procedures.

  2. On the mornings of the PK-1, PK-2, Expt. 1 or Expt. 2 experimental procedures:

     1. Use of any medications or substances that may increase the risk of IV Allo side effects or adversely affect the experimental results (indicated by report, urine toxicology, urine nicotine/cotinine testing, or urine alcohol testing) will be exclusionary.
     2. Systemic hormone therapy or contraception will be exclusionary [Exception: Hormonal IUDs (e.g., Mirena, Kyleena, Liletta, and Skyla) or other contraceptive devices (e.g., Nuvaring)] will be allowed if the participant still has normal menstrual periods and is found to ovulate using commercial urine test kits provided by study).

• 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).

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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96 participants in 4 patient groups, including a placebo group

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

Experimental group

Description:

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.

Treatment:

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.

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 group

Description:

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.

Treatment:

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

Other: Matching IV Placebo

Other: Matching IV Placebo

IV Allo for Reconsolidation Blockade (Expt. 2)

Experimental group

Description:

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+).

Treatment:

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.

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

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 group

Description:

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+).

Treatment:

Other: Matching IV Placebo

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

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

Other: Matching IV Placebo