Facilitation of Extinction Retention and Reconsolidation Blockade by IV Allopregnanolone in PTSD- Pharmacokinetic Studies
| Registry | NCT04468360 |
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| Status | Terminated - The investigator moved to another institution; only preliminary data from pharmacokinetic studies were collected at Boston University School of Medicine/Boston Medical Center. |
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| Phase | Phase 2 |
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| Study type | Interventional; non randomized, sequential, masking: none, other |
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| Enrollment | 11 (Actual) |
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| Sponsor | Boston University (Other); collaborators: National Institute of Mental Health (NIMH) |
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| Conditions | Pharmacokinetic Study, Post Traumatic Stress Disorder |
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| Interventions | PK-1 Good Manufacturing Practices (GMP) allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis, PK-2 GMP allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis. (Drug) |
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| Dates | start 2022-03-04, primary completion 2025-04-29, completion 2025-04-29, first posted 2020-07-13, last updated 2026-06-02 |
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| Locations | 1 site in United States |
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Related Papers Related Patents Related Grants Related Experts
All trials for Pharmacokinetic Study All trials for Post Traumatic Stress Disorder All trials of PK-1 Good Manufacturing Practices (GMP) allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis All trials of PK-2 GMP allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis.
-Summary
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 to prevent them from triggering intense, distressing, disruptive, out-of-place responses.
Before starting the interventional study (described in detail in NCT07079761), the investigators will conduct two pharmacokinetic (PK) studies (PK-1 and PK-2) in a small group of individuals with PTSD to test dosing and safety at Boston Medical Center.
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+Arms and interventions
| Arm | Type | Interventions | Description |
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| PK-1 Group | Experimental | Drug: PK-1 Good Manufacturing Practices (GMP) allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis | Participants assigned to this group received IV allopregnanolone as a 5-minute loading dose at 1.7 mcg/kg followed by a maintenance infusion at 2.6 mcg/kg/hr over the next 4-5 hours intended to optimize resting plasma allopregnanolone + pregnanolone levels while outcomes were measured. |
| PK-2 Group | Experimental | Drug: PK-2 GMP allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis. | Participants assigned to this group received a 30-minute drug infusion of IV allopregnanolone of 28 mcg/kg, The IV allopregnanolone then was discontinued and only normal saline was continued for the next 4-5 hours while outcomes were measured. |
- PK-1 Good Manufacturing Practices (GMP) allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis (Drug), also known as U.S.P. equivalent: brexanolone (IV Allopregnanolone with Captisol) (SAGE Therapeutics): For the PK-1 group, after the 5-minute loading dose of IV allopregnanolone, the dose was changed as prescribed to optimize the subject's target plasma allopregnanolone + pregnanolone level for the next 4-5 hours.
- PK-2 GMP allopregnanolone (Allo) with Dexolve in 0.9% saline for infusion manufactured by the University of California, Davis. (Drug), also known as U.S.P. equivalent: brexanolone (IV allopregnanolone with Captisol) (SAGE Therapeutics): For the PK-2 group, after the 30-minute drug infusion of IV allopregnanolone, the IV allopregnanolone was discontinued and only normal saline was continued for the next 4-5 hours.
+Outcome measures
Primary outcomes
- Clinician Assessed Sedation Levels for Each Participant [resting pre-infusion; after loading dose at 0 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 300 minutes]: Sedation levels will be assessed with the Qualitative Sedation Rating Scale. It has 5 categories: None- responds normally to verbal commands, cognitive \& coordination not impaired, ventilatory \& cardiovascular functions unaffected; Minimal- responds normally to verbal commands, unaffected ventilatory \& cardiovascular functions, mild feelings of intoxication, cognitive function \& coordination may be impaired; Moderate-responds purposefully to commands alone or with light touch, protective airway reflexes \& adequate ventilation maintained without intervention, cardiovascular function remains stable; Deep- cannot be easily aroused but responds purposefully to noxious stimulation, assistance may be needed to ensure the airway is protected \& adequate ventilation maintained, cardiovascular function is usually stable; Dissociative- trance-like cataleptic state with profound analgesia \& amnesia, airway protective reflexes, spontaneous respirations \& cardiopulmonary stability retained.
- Blood Oxygen Saturation [resting pre-infusion; after loading dose at 0 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 300 minutes]: Average across participants of blood oxygen saturation levels obtained via pulse oximetry (ranging from 0% to 100%) for each time point indicated.
- Respiratory Rate [resting pre-infusion; after loading dose at 0 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 300 minutes]: Average across participants of respiratory rate for each time point indicated.
- Pulse Rate [resting pre-infusion; after loading dose at 0 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 300 minutes]: Average across participants of pulse rate for each time point indicated.
- Diastolic Blood Pressure [resting pre-infusion; after loading dose at 0 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 300 minutes]: Average across participants of diastolic blood pressure for each time point indicated.
- Systolic Blood Pressure [resting pre-infusion; after loading dose at 0 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 300 minutes]: Average across participants of systolic blood pressure for each time point indicated.
+Eligibility
Sex: All, ages: 18 Years to 55 Years
Inclusion Criteria:
* Chronic Posttraumatic Stress Disorder
* 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
* Females: must have a menstrual cycle and not be on hormonal birth control (with a few exceptions; see below)
* If gender non-conforming: must not be on hormone therapy
Exclusion Criteria:
* Bipolar I disorder, schizophreniform disorder, or clinically significant psychotic symptoms apart from the presence of trauma-related sensory hallucinations or negative beliefs
* Moderate or severe substance use disorder within three months of screening
* Sleep Apnea
* History of a suicide attempt within 1 year of enrolling
* Imminent risk to self or others or requiring clinical intervention to maintain safety
* Unstable medical condition or condition that may affect outcomes
* Moderate or severe traumatic brain injury (TBI) (mild TBI acceptable; moderate TBI allowed for PK study)
* Using any medications or substances (per self-report or toxicology testing) that may increase the risk for IV Allo side effects or affect the experimental results.
* Unable to tolerate IV placement or blood drawing by needle stick
* Wear hearing aids or fail hearing test (not applicable to PK study)
* Females: pregnant, breastfeeding, or if of childbearing potential, unwilling to use two forms of effective birth control \[except for hormonal contraceptives, unless intrauterine device (IUD) or a device like NuvaRing\] for one week before and one month after study drug administration
+Posted results
Participant flow
| Milestone | PK-1 Group | PK-2 Group |
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| Started | 6 | 5 |
| Completed | 6 | 5 |
| Not completed | 0 | 0 |
Outcome results
- Clinician Assessed Sedation Levels for Each Participant (Primary), Count of participants, Participants: PK-1 Group 6; PK-2 Group 5
- Blood Oxygen Saturation (Primary), Mean, percent oxygen saturation: PK-1 Group 98.3 +/- 1.4; PK-2 Group 98.6 +/- 1.3
- Respiratory Rate (Primary), Mean, respirations per minute: PK-1 Group 14.8 +/- 3.0; PK-2 Group 14.2 +/- 2.7
- Pulse Rate (Primary), Mean, number of heart beats/minute: PK-1 Group 71.7 +/- 9.4; PK-2 Group 68.8 +/- 5.1
- Diastolic Blood Pressure (Primary), Mean, mm Hg: PK-1 Group 79.0 +/- 7.4; PK-2 Group 74.0 +/- 11.3
- Systolic Blood Pressure (Primary), Mean, mmHg: PK-1 Group 123.7 +/- 14.5; PK-2 Group 110.0 +/- 13.3
Adverse events
Time frame: 4-5 hours
| Arm | Deaths | Serious adverse events | Other adverse events |
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| PK-1 Group | 0/6 (0.0%) | 0/6 (0.0%) | 0/6 (0.0%) |
| PK-2 Group | 0/5 (0.0%) | 0/5 (0.0%) | 0/5 (0.0%) |
Limitations and caveats: Only preliminary data from pharmacokinetic studies were collected at Boston University School of Medicine/Boston Medical Center before the investigator moved to another institution where the actual research study is being conducted \[refer to NCT07079761\].
+Locations (1)
| Facility | City | Country | Status |
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| Boston University Chobanian & Avedisian School of Medicine | Boston, Massachusetts | United States | |
+Publications
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- Elsey JWB, Van Ast VA, Kindt M. Human memory reconsolidation: A guiding framework and critical review of the evidence. Psychol Bull. 2018 Aug;144(8):797-848. doi: 10.1037/bul0000152. Epub 2018 May 24. PMID 29792441
- Glover EM, Jovanovic T, Mercer KB, Kerley K, Bradley B, Ressler KJ, Norrholm SD. Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder. Biol Psychiatry. 2012 Jul 1;72(1):19-24. doi: 10.1016/j.biopsych.2012.02.031. Epub 2012 Apr 12. PMID 22502987
- Hu H, Real E, Takamiya K, Kang MG, Ledoux J, Huganir RL, Malinow R. Emotion enhances learning via norepinephrine regulation of AMPA-receptor trafficking. Cell. 2007 Oct 5;131(1):160-73. doi: 10.1016/j.cell.2007.09.017. PMID 17923095
- Jovanovic T, Kazama A, Bachevalier J, Davis M. Impaired safety signal learning may be a biomarker of PTSD. Neuropharmacology. 2012 Feb;62(2):695-704. doi: 10.1016/j.neuropharm.2011.02.023. Epub 2011 Mar 4. PMID 21377482
- Mamiya N, Fukushima H, Suzuki A, Matsuyama Z, Homma S, Frankland PW, Kida S. Brain region-specific gene expression activation required for reconsolidation and extinction of contextual fear memory. J Neurosci. 2009 Jan 14;29(2):402-13. doi: 10.1523/JNEUROSCI.4639-08.2009. PMID 19144840
- Maren S. Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala. Brain Res. 2015 Sep 24;1621:231-8. doi: 10.1016/j.brainres.2014.10.010. Epub 2014 Oct 12. PMID 25312830
- Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res. 2008 Jun;42(7):515-20. doi: 10.1016/j.jpsychires.2008.01.017. Epub 2008 Feb 29. PMID 18313695
- Milad MR, Zeidan MA, Contero A, Pitman RK, Klibanski A, Rauch SL, Goldstein JM. The influence of gonadal hormones on conditioned fear extinction in healthy humans. Neuroscience. 2010 Jul 14;168(3):652-8. doi: 10.1016/j.neuroscience.2010.04.030. Epub 2010 Apr 22. PMID 20412837
- Monfils MH, Cowansage KK, Klann E, LeDoux JE. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science. 2009 May 15;324(5929):951-5. doi: 10.1126/science.1167975. Epub 2009 Apr 2. PMID 19342552
- Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature. 2000 Aug 17;406(6797):722-6. doi: 10.1038/35021052. PMID 10963596
- Norrholm SD, Anderson KM, Olin IW, Jovanovic T, Kwon C, Warren VT, McCarthy A, Bosshardt L, Sabree J, Duncan EJ, Rothbaum BO, Bradley B. Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear. Front Behav Neurosci. 2011 Nov 21;5:77. doi: 10.3389/fnbeh.2011.00077. eCollection 2011. PMID 22125516
- Norrholm SD, Jovanovic T, Olin IW, Sands LA, Karapanou I, Bradley B, Ressler KJ. Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity. Biol Psychiatry. 2011 Mar 15;69(6):556-63. doi: 10.1016/j.biopsych.2010.09.013. Epub 2010 Oct 29. PMID 21035787
- Oh MC, Derkach VA, Guire ES, Soderling TR. Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem. 2006 Jan 13;281(2):752-8. doi: 10.1074/jbc.M509677200. Epub 2005 Nov 4. PMID 16272153
- Orr SP, Metzger LJ, Lasko NB, Macklin ML, Peri T, Pitman RK. De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. J Abnorm Psychol. 2000 May;109(2):290-8. PMID 10895567
- Orr SP, Milad MR, Metzger LJ, Lasko NB, Gilbertson MW, Pitman RK. Effects of beta blockade, PTSD diagnosis, and explicit threat on the extinction and retention of an aversively conditioned response. Biol Psychol. 2006 Oct;73(3):262-71. doi: 10.1016/j.biopsycho.2006.05.001. Epub 2006 Jul 7. PMID 16828533
- Pineles SL, Nillni YI, King MW, Patton SC, Bauer MR, Mostoufi SM, Gerber MR, Hauger R, Resick PA, Rasmusson AM, Orr SP. Extinction retention and the menstrual cycle: Different associations for women with posttraumatic stress disorder. J Abnorm Psychol. 2016 Apr;125(3):349-55. doi: 10.1037/abn0000138. Epub 2016 Feb 11. PMID 26866677
- Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, Milad MR, Liberzon I. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci. 2012 Nov;13(11):769-87. doi: 10.1038/nrn3339. Epub 2012 Oct 10. PMID 23047775
- Rasmusson AM, Pineles SL. Neurotransmitter, Peptide, and Steroid Hormone Abnormalities in PTSD: Biological Endophenotypes Relevant to Treatment. Curr Psychiatry Rep. 2018 Jul 17;20(7):52. doi: 10.1007/s11920-018-0908-9. PMID 30019147
- Tronson NC, Wiseman SL, Olausson P, Taylor JR. Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A. Nat Neurosci. 2006 Feb;9(2):167-9. doi: 10.1038/nn1628. Epub 2006 Jan 15. PMID 16415868
- Zuj DV, Palmer MA, Hsu CM, Nicholson EL, Cushing PJ, Gray KE, Felmingham KL. IMPAIRED FEAR EXTINCTION ASSOCIATED WITH PTSD INCREASES WITH HOURS-SINCE-WAKING. Depress Anxiety. 2016 Mar;33(3):203-10. doi: 10.1002/da.22463. Epub 2016 Jan 6. PMID 26744059
+Study documents
+Investigators
- Ann M Rasmusson, MD, Principal investigator, Boston University Chobanian & Avedisian School of Medicine, Dept of Psychiatry
+Funding