How to Treat Post-Traumatic Stress Disorder

Abstract

The present disclosure provides a method for treating disease or disorder by administering pharmaceutical compounds.In particular, the present disclosure relates to treating post-traumatic stress disorder in individuals who need such treatment by administering fatty acid amide hydrolase inhibitor or its pharmacologic acceptable salt.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 229,387, filed August 4, 2021, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Post-traumatic stress disorder (PTSD) is a common mental condition that can result from direct or indirect exposure to actual or threatened death, serious injury, or sexual violence (APA 2013). Approximately 70% of the world's population will experience a traumatic event at some point during their lifetime, with the majority recovering within days to weeks of traumatic exposure (Kessler 2017). However, 4.7%-6.1% of people in the United States will develop PTSD (Goldstein 2016), and similar rates are observed in the European Union (0.6%-6.7%) (Burri and Maercker 2014). While men are more likely to experience a traumatic event, women are twice as likely to develop PTSD (Goldstein 2016, Kessler 2017).

[0003] Post-traumatic stress disorder is characterized by symptoms experienced after a potentially traumatic event (Hoffman 2018). PTSD symptoms are grouped into four symptom clusters: 1) recurrent intrusion / re-experiencing, 2) persistent avoidance, 3) negative changes in mood and cognition, and 4) marked arousal / reactivity. A traumatic event is defined as extreme or repeated exposure to actual or threatened death, serious injury, or sexual violence experienced directly, witnessed, or learned about happening to a loved one, or to aversive details through work (e.g., first responders) (APA 2013). In addition to increased risk of mortality, PTSD also has a significant impact on how patients feel and function. Post-traumatic stress disorder affects all aspects of patients' lives, including negative impacts on work, school, relationships, housing, legal issues, financial issues, and an overall increase in health care utilization and costs (Kessler 2017, Watson 2019). A variety of guidelines exist for the treatment of PTSD (APA 2004, NICE 2018, VA / DoD 2003, ISTSS 2018), most of which include guidance for psychological and pharmacological treatments. There is an urgent need to address significant gaps in progress in pharmacotherapy treatment for PTSD (Krystal 2017). Summary of the Invention

[0004] In some aspects, a method for treating post-traumatic stress disorder is provided herein.Various embodiments are contemplated herein.In some embodiments, a method for treating post-traumatic stress disorder (PTSD) in an individual in need of such treatment is provided, comprising administering to the individual an oral dosage form of Compound A or a pharma-ceutically acceptable salt thereof: [ka] once daily (QD) for a period of at least 8 weeks.

[0005] In some embodiments, the oral dosage form is a solid. In certain variations, the oral dosage form contains at least 0.3 mg of Compound A. In certain variations, the oral dosage form contains between 0.3 mg and 4 mg of Compound A.

[0006] In some embodiments, the period is at least 12 weeks. In some variations, the oral dosage form of Compound A is administered to the individual in an amount effective to achieve a plasma concentration of Compound A of 1 ng / ml to 3 ng / ml. In other variations, the oral dosage form of Compound A is administered to the individual in an amount effective to maintain a plasma concentration of Compound A of at least 1 ng / ml for at least 12 hours. In yet other variations, the oral dosage form of Compound A is administered to the individual in an amount effective to achieve a plasma concentration of the endocannabinoid anandamide (AEA) of 2 ng / ml to 5 ng / ml. In certain variations, the oral dosage form of Compound A is administered to the individual in an amount effective to maintain a plasma concentration of the endocannabinoid anandamide (AEA) of at least 2 ng / ml for at least 12 hours.

[0007] In some embodiments, the individual in need of treatment is an adult. In one variation, the individual is a human. In certain embodiments, the individual in need of treatment has a genetic predisposition to PTSD. [Brief description of the drawings]

[0008] [Figure 1] Schema of a double-blind, placebo-controlled, randomized, parallel-group study of the safety and efficacy of Compound A in treating adult participants with PTSD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] definition As used herein, "treatment" or "treating" refers to an approach to obtain a beneficial or desired outcome. In the context of PTSD, a beneficial or desired outcome can include reducing or alleviating one or more symptoms associated with post-traumatic stress disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), including, but not limited to, recurrent intrusions or re-experiencing, persistent avoidance, negative changes in mood and cognition, and marked arousal or reactivity, or improving the patient's quality of life.

[0010] As used herein, "pharmacologically acceptable" refers to a substance that is not biologically or otherwise undesirable, e.g., a substance may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. A pharma-ceutically acceptable carrier or excipient preferably meets the necessary standards of toxicity and manufacturing testing and / or is included in the inactive ingredients guide prepared by the US Food and Drug administration.

[0011] As used herein, "oral dosage form" refers to any formulation suitable for oral administration.

[0012] As used herein, "individual" refers to a mammal (eg, a human) in need of treatment.

[0013] The term "adult" refers to an individual aged 18 or older.

[0014] Reference herein to "about" a value or parameter includes (and accounts for) the variation that is directed to that value or parameter itself.

[0015] The singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0016] The term "comprise" or variations such as "comprises" or "comprising" are understood to imply the inclusion of a stated element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0017] The embodiments described herein include "consisting of" and / or "consisting essentially of" aspects.

[0018] This application refers to various issued patents, published patent applications, journal articles, and other publications, each of which is incorporated herein by reference for all purposes.

[0019] Compound A Compound A, also known as PF-04457845, is an orally available, highly selective, and irreversible inhibitor of fatty acid amide hydrolase (FAAH) (Ahn 2011, Johnson 2011, Bonifacio 2020). Compound A is chemically described as N-pyridazin-3-yl-4-{3-[5-(trifluoromethyl)-2-pyridyloxy]benzylidene}piperidine-1-carboxamide, having the following structural formula: [ka] Compound A is disclosed in U.S. Patent No. 8,044,052, entitled "Biaryl Ether Urea Compounds," which is incorporated herein by reference in its entirety. Descriptions of Compound A and methods of making Compound A can be found, for example, in column 35, Example 5a and column 36, Example 5b of the above-referenced patent, which sections are specifically incorporated herein by reference.

[0020] A recent investigator-initiated placebo-controlled study showed that Compound A enhanced fear extinction memory recall and blunted negative effects in response to aversive stimuli in healthy volunteers. See, e.g., Mayo et al. Biological Psychiatry 2020, 87:538-547. Another study found that Compound A significantly increased slow-wave sleep measured by polysomnography and improved overall self-reported sleep compared to placebo in men with cannabis use disorder (CUD) (see, e.g., D'Souza et al. The Lancet Psychiatry 2019, 6:35-45). Compound A is also undergoing clinical evaluation for the treatment of cannabis withdrawal and cannabis use disorder (see, e.g., NCT01618656 and NCT03386487).

[0021] method Provided herein is a method of treating post-traumatic stress disorder (PTSD) in an individual in need of such treatment, comprising administering to the individual an oral dosage form of Compound A or a pharma- ceutically acceptable salt thereof. To achieve treatment, the oral dosage form may be given to the individual for any period of time (e.g., at least or about 4 weeks, 8 weeks, 12 weeks, 4 months, 6 months, 1 year, etc.). The oral dosage form may contain any amount of Compound A (e.g., at least or about 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, etc.). Treatment may reduce or alleviate one or more DSM-5 defined symptoms associated with post-traumatic stress disorder, including, but not limited to, recurrent intrusions or re-experiencing, persistent avoidance, negative changes in mood and cognition, and significant arousal or reactivity.

[0022] The oral dosage form may be given to an individual for any period of time to achieve treatment. In some embodiments, the period is at least 8 weeks in duration. In some embodiments, the period is at least 12 weeks in duration. In some embodiments, the period is 1-3 months in duration. In some embodiments, the period is 3-6 months in duration. In some embodiments, the period is 1 year in duration.

[0023] In some embodiments, in conjunction with the above or below embodiments, the oral dosage form is administered to the individual for a period of about 4 weeks. In some embodiments, in conjunction with the above or below embodiments, the oral dosage form is administered to the individual for a period of about 2 weeks. In some embodiments, in conjunction with the above or below embodiments, the oral dosage form is administered to the individual for a period of about 1 week.

[0024] The oral dosage form may contain any amount of compound A or a pharma- ceutically acceptable salt thereof to achieve treatment. In some embodiments, the oral dosage form contains at least or about 0.3 mg of compound A. In some embodiments, the oral dosage form contains about 0.3 mg to about 4 mg of compound A. In some embodiments, the oral dosage form contains about 0.5 mg to 4 mg, or 1 mg to 4 mg, or 2 mg to 4 mg, or 3 mg to 4 mg, or 2 mg to 3 mg of compound A. In some embodiments, the oral dosage form contains at least or about 4 mg (e.g., at least or about 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg) of compound A. In some embodiments, the oral dosage form contains about 4 mg to 5 mg, or 4 mg to 6 mg, or 4 mg to 7 mg, or 4 mg to 8 mg, or 4 mg to 9 mg, or 4 mg to 10 mg of compound A.

[0025] In some embodiments, the method includes administering an amount of compound A effective to achieve a minimum effective concentration (MEC) of compound A or an active metabolite thereof in plasma. In some embodiments, the MEC of compound A is at least about 1 ng / ml. In some embodiments, the MEC of compound A is at least or about any one of 1 ng / ml, 1.5 ng / ml, 2 ng / ml, 2.5 ng / ml, 3 ng / ml, 3.5 ng / ml, 4 ng / ml, 4.5 ng / ml, 5 ng / ml, 5.5 ng / ml, 6 ng / ml, 7 ng / ml, 8 ng / ml, 9 ng / ml, or 10 ng / ml. In some embodiments, the MEC of compound A is about 1 ng / ml to about 2 ng / ml. In some embodiments, the MEC of Compound A is any one of about 1 ng / ml to 2 ng / ml, 1 ng / ml to 3 ng / ml, 1 ng / ml to 4 ng / ml, 1 ng / ml to 5 ng / ml, 1 ng / ml to 6 ng / ml, 1 ng / ml to 7 ng / ml, 1 ng / ml to 8 ng / ml, 1 ng / ml to 9 ng / ml, or 1 ng / ml to 10 ng / ml. In some embodiments, the method includes administering an amount of Compound A effective to maintain the MEC of Compound A for a duration of time (e.g., at least 6 hours, 12 hours, 15 hours, 18 hours, 24 hours, etc.). For example, in some embodiments, the MEC of Compound A is any one of about 1 ng / ml to 2 ng / ml, 1 ng / ml to 3 ng / ml, 1 ng / ml to 4 ng / ml, 1 ng / ml to 5 ng / ml, 1 ng / ml to 6 ng / ml, 1 ng / ml to 7 ng / ml, 1 ng / ml to 8 ng / ml, 1 ng / ml to 9 ng / ml, 1 ng / ml to 10 ng / ml, which is maintained for a duration of at least 6 hours, 12 hours, 15 hours, 18 hours, or any one of 24 hours. In some embodiments, administration of Compound A includes administration of an oral dosage form. In some embodiments, the oral dosage form is administered once daily to achieve a desired MEC for a duration of at least or about 6 hours, 12 hours, 15 hours, 18 hours, or 24 hours.

[0026] In some embodiments, the method comprises administering an amount of compound A effective to achieve a plasma minimum effective concentration (MEC) of the endocannabinoid anandamide (AEA). In some embodiments, the MEC of AEA is at least about 2 ng / ml. In some embodiments, the MEC of AEA is at least or about any one of 2 ng / ml, 2.5 ng / ml, 3 ng / ml, 3.5 ng / ml, 4 ng / ml, 4.5 ng / ml, 5 ng / ml, 5.5 ng / ml, 6 ng / ml, 7 ng / ml, 8 ng / ml, 9 ng / ml, or 10 ng / ml. In some embodiments, the MEC of AEA is about 2 ng / ml to about 3 ng / ml. In some embodiments, the MEC of AEA is any one of about 2ng / ml to 3ng / ml, 2ng / ml to 4ng / ml, 2ng / ml to 5ng / ml, 2ng / ml to 6ng / ml, 2ng / ml to 7ng / ml, 2ng / ml to 8ng / ml, 2ng / ml to 9ng / ml, or 2ng / ml to 10ng / ml. In some embodiments, the method includes administering an amount of Compound A effective to maintain the MEC of AEA for a duration of time (e.g., at least or about 6 hours, 12 hours, 15 hours, 18 hours, 24 hours, etc.). For example, in some embodiments, the MEC of AEA is at least or about one of 2 ng / ml, 2.5 ng / ml, 3 ng / ml, 3.5 ng / ml, 4 ng / ml, 4.5 ng / ml, 5 ng / ml, 5.5 ng / ml, 6 ng / ml, 7 ng / ml, 8 ng / ml, 9 ng / ml, or 10 ng / ml, maintained for a duration of at least or about any one of 6 hours, 12 hours, 15 hours, 18 hours, or 24 hours.

[0027] In some embodiments, the individual in need of treatment is diagnosed with PTSD. For example, PTSD may be diagnosed using the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In some embodiments, the PTSD diagnosis may be confirmed using the Mini International Neuropsychiatric Interview (MINI). The MINI is a short, structured, clinician-administered diagnostic interview for psychiatric disorders (Sheehan 1998). The MINI assessment may be used to confirm the PTSD diagnosis. In some embodiments, the PTSD diagnosis may be confirmed by CAPS-5. In some embodiments, the individual may be diagnosed with PTSD using the DSM-5, the MINI, the CAPS-5, or any combination thereof.

[0028] In some embodiments, the individual in need of treatment has a PCL-5 total score of at least 30 (e.g., at least 30, 31, 32, 33, 34, 35, 40, 45, 50, etc.). In some embodiments, the individual in need of treatment has a PCL-5 total score of at least 35. In some embodiments, the individual in need of treatment has a co-occurring diagnosis of major depressive disorder, persistent depressive disorder, generalized anxiety disorder, specific phobia, obsessive-compulsive disorder, social anxiety disorder, or any combination thereof. In some embodiments, the individual in need of treatment has been treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) prior to the PTSD treatment using Compound A (e.g., receiving a stable dose of an SSRI or SNRI at least 8 weeks prior to treatment). In some embodiments, the PTSD treatment using Compound A is an add-on therapy administered to an individual receiving treatment with an SSRI or SNRI. In some embodiments, the PTSD treatment using Compound A is an add-on therapy administered to an individual receiving treatment with an SSRI. In some embodiments, the PTSD treatment using Compound A is an add-on therapy administered to an individual receiving treatment with an SNRI. In some embodiments, the PTSD treatment using Compound A is a monotherapy administered to an individual. In some embodiments, the PTSD treatment using Compound A is administered to an individual not concurrently receiving treatment with an SSRI or SNRI.

[0029] In some embodiments, the individual in need of treatment has a genetic predisposition to PTSD. In some embodiments, the individual in need of treatment is an adult. In some embodiments, the individual in need of treatment is an adult male. In some embodiments, the individual in need of treatment is an adult female.

[0030] Efficacy evaluation In some embodiments, the treatment may be effective to achieve an improvement in one or more of the following assessments: CAPS-5, CGI-S, CGI-C, PGI-S, PCL-5, B-IPF, ReQoL-10, SDS, PSQI-A, ISI, PHQ-9, and SIGH-A. In some embodiments, the treatment may be effective to achieve an improvement in CAPS-5, CGI-S, PGI-S, or any combination thereof. For example, the treatment may be effective to achieve a change in CAPS-5 of at least 5 points (e.g., 5, 6, 7, 8, 9, 10, 15, 20 points, etc.). In some embodiments, the treatment may be effective to achieve a change in one or more CAPS-5 items (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 CAPS-5 items, etc.) of at least 1 point. In some embodiments, treatment may be effective to achieve at least a 30% (e.g., 30%, 35%, 40%, 45%, 50%, or more) improvement in CAPS-5 total symptom severity score. In some embodiments, treatment may be effective to achieve a very large or large improvement in CGI-S. In some embodiments, treatment may be effective to achieve at least a 1 unit (e.g., 1, 2, 3, 4, 5 units, etc.) improvement in PGI-S.

[0031] In some embodiments, the efficacy of treatment may be assessed by the Clinician Administered PTSD Scale (CAPS-5). The CAPS-5 is a structured, clinician-administered clinical interview in which participants report on their PTSD symptoms (Weathers 2018). The CAPS-5 may be administered by a qualified medical professional (e.g., PI, clinical assessor). It is a well-established, widely used, and valid assessment that captures the frequency and intensity of PTSD symptoms over the past week using a 5-point Likert-type rating scale. Its unique features include standardized prompts, ratings of symptom frequency, intensity, and severity, and behaviorally anchored ratings. The CAPS-5 total symptom severity score is derived by summing the scores of items 1-20. Each item is rated with a single severity score on a 5-point rating scale (0-4) that corresponds to the following categories: 0 absent, 1 mild / below threshold, 2 moderate / threshold, 3 severe / markedly elevated, and 4 extreme / unable to live normally. The CAPS-5 total symptom severity score can range from 0 to 80.

[0032] In some embodiments, the efficacy of treatment may be assessed by the Clinical Global Impression of Severity (CGI-S). The CGI-S is a 7-point Likert-type rating scale, a widely used assessment in clinical psychopharmacology trials to assess the severity of illness (Guy 1976). Responses on this investigator-completed scale range from 1 (normal, not sick at all) to 7 (one of the sickest patients). Qualified medical personnel rate the impression of the severity of the participant's current ability to function due to PTSD relative to their experience with this patient population. In some embodiments, the CGI-S may be used to assess the severity of an individual's PTSD.

[0033] In some embodiments, the efficacy of treatment may be assessed by the Clinical Global Impression of Change (CGI-C). The CGI-C is a 7-point Likert-type rating scale, a widely used assessment to evaluate efficacy in clinical drug trials (Guy 1976). The investigator or trained assessor evaluates the impression of any change in the severity of the individual's condition since baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worsened). The assessment focuses on the change in the individual's ability to function due to PTSD.

[0034] In some embodiments, the efficacy of treatment may be assessed by the Patient Global Impression of Severity (PGI-S). The PGI-S is a 5-point Likert-type rating scale, a widely used assessment in clinical psychopharmacology trials to assess illness severity. Responses on this patient-completed scale range from 1=none to 5=very severe. Individuals may report the severity of their PTSD symptoms.

[0035] In some embodiments, the efficacy of treatment may be assessed by the Brief Inventory of Psychosocial Functioning (B-IPF). The B-IPF is a seven-item self-report questionnaire that assesses PTSD-related psychosocial dysfunction (Kleiman 2018). Questions about dysfunction are rated on a six-point scale ranging from 0 (not at all), to 1-5 (somewhat), to 6 (extremely).

[0036] In some embodiments, the efficacy of treatment may be assessed by the Sheehan Disability Scale (SDS). The SDS is a brief 5-item self-report tool that assesses impairment in work / school, social life, and family life (Leon 1997). Total scores range from 0 to 30 (0: no impairment, 30: severe impairment). Higher scores are associated with significant impairment.

[0037] In some embodiments, the efficacy of treatment may be assessed by the PTSD Checklist (PCL-5). The PCL-5 is a 20-item self-report scale assessing the 20 DSM-5 symptoms of PTSD. It can be used to monitor symptom change during and after treatment (Blevins 2015).

[0038] In some embodiments, the efficacy of treatment may be assessed by the Insomnia Severity Index (ISI). The ISI is a seven-item self-report questionnaire that assesses the nature, severity, and impact of insomnia (Morin 2011). The dimensions assessed are the severity of problems with sleep onset, sleep maintenance, and early morning awakening, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, the conspicuousness of sleep disturbances by others, and distress caused by sleep difficulties. A five-point Likert scale is used to rate each item.

[0039] In some embodiments, the efficacy of treatment may be assessed by the Pittsburgh Sleep Quality Index-PTSD Addendum (PSQI-A). The PSQI-A is a 19-item self-report questionnaire that assesses sleep quality and disturbances over the past month (Insana 2013). The PSQI-A is composed of seven different sleep disturbance items commonly reported by adults with PTSD (e.g., hot flashes, memories or nightmares of the traumatic experience, and episodes of terror during sleep). Items are rated on a 0 (none in the past month) to 3 (three or more times per week) point scale and can be summed to create a total score. The total score can range from 0 (normal) to 21 (severe).

[0040] In some embodiments, the efficacy of treatment may be assessed by the Patient Health Questionnaire (PHQ-9). The PHQ-9 is a component of the longer Patient Health Questionnaire and is a brief self-administered tool for assessing depression (Kroenke 2001). It incorporates DSM depression criteria with other major depressive symptoms into a brief self-report instrument that is commonly used for screening and diagnosis, as well as treatment selection and monitoring.

[0041] In some embodiments, the efficacy of treatment may be assessed by the Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A). The SIGH-A is a clinician-administered rating scale developed to measure the severity of anxiety symptoms (Hamilton 1959). The scale consists of 14 items, each defined by a set of symptoms, measuring both mental anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety).

[0042] In some embodiments, the efficacy of treatment may be assessed by Recovering Quality of Life (ReQoL). The ReQoL-10 is a patient-reported outcome developed to assess the quality of life of people with different mental health conditions (Keetharuth 2018). It is suitable for use across all mental health populations, including common mental health issues.

[0043] Administration In some embodiments, the oral dosage form can be a solid (e.g., a tablet or capsule). In some embodiments, the oral dosage form can be a liquid. In some embodiments, the oral dosage form is administered to the individual once a day (QD). In some embodiments, the oral dosage form is administered to the individual in the morning (e.g., any time between about 6 a.m. and about noon). In some embodiments, the oral dosage form is administered to the individual within about four hours of waking (e.g., within about 4, 3, 2, or 1 hours). In some embodiments, the oral dosage form is administered to the patient QD in the morning with or without food (e.g., with or without food).

[0044] Other routes of administration may also be used, including, but not limited to, parenteral (eg, intravenous, subcutaneous, intramuscular, intraperitoneal, or intrapleural) and transdermal routes of administration. EXAMPLES

[0045] Example 1. A Phase 2 Study to Evaluate the Safety and Efficacy of Compound A in the Treatment of Adults with PTSD research design This study is a 12-week, double-blind, placebo-controlled, randomized, parallel-group study of the safety and efficacy of Compound A in treating adult participants with PTSD. The objective of this Phase 2 study is to provide an evaluation of the efficacy and safety of Compound A in participants with PTSD while evaluating a wide range of Compound A doses to support pharmacokinetic (PK) / pharmacodynamic (PD) exposure-response analysis.

[0046] Participants who meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for PTSD as determined by the Mini International Neuropsychiatric Interview (MINI), with a total PCL-5 score ≥ 35 at screening and baseline, will be eligible for enrollment. PTSD diagnosis must be confirmed by CAPS-5 administered at baseline. After screening, eligible participants (approximately 270 participants) will be randomized (2:1:2) to one of three treatment arms: placebo, Compound A 0.3 mg QD, or Compound A 4 mg QD. Randomization will be stratified based on the presence vs. absence of stable selective SSRI / serotonin norepinephrine reuptake inhibitor (SNRI) use at screening. Sponsors, investigators, clinical assessors, and participants will be blinded to treatment assignment.

[0047] The study will consist of the following periods: screening period and prohibited drug washout (up to 28 days), baseline and randomization (Day 1), double-blind treatment period (12 weeks, e.g., Weeks 1-12), and safety follow-up (2 weeks, e.g., 14 days after the last dose). During the 12-week treatment period, clinical visits will occur at weeks 1, 4, 8, and 12. The study schema is shown in the figure.

[0048] Study population Participants are eligible for inclusion in the study only if all of the following criteria apply: 1. Participants must be between 18 and 70 years of age at the time of signing the informed consent. 2. Participants must be outpatients with a primary diagnosis of DSM-5-defined PTSD based on the MINI at screening and confirmed by CAPS-5 at baseline. 3. PCL-5 total score ≥ 35 at screening and baseline. 4. PTSD must be the primary diagnosis. Participants with a co-occurring diagnosis of major depressive disorder (excluding current severe symptoms), persistent depressive disorder (formerly known as dysthymia), generalized anxiety disorder, specific phobia, obsessive-compulsive disorder (excluding severe symptoms), or social anxiety disorder are eligible if PTSD is the primary diagnosis. 5. Participants prescribed an SSRI or SNRI must not plan to change the dose or treatment regimen during the course of the study and must be receiving a stable dose for at least 8 weeks prior to screening. Participants not receiving an SSRI / SNRI at screening must not begin treatment with an SSRI / SNRI during the course of the study.

[0049] Research objectives and evaluation The primary objective of this study is to evaluate the efficacy of Compound A, administered once daily at doses of 0.3 mg and 4 mg for up to 12 weeks, compared to placebo in treating adults with PTSD, as measured by change in CAPS-5 total symptom severity score. The primary evaluand variable is the change from baseline to week 12 in the Clinician Administered PTSD Scale (CAPS-5) total symptom severity score.

[0050] The primary secondary objective of this study is to evaluate the efficacy of Compound A administered once daily at doses of 0.3 mg and 4 mg over 12 weeks compared to placebo on overall clinician and patient global impression of severity. Key secondary evaluative outcomes include: 1) change from baseline to week 12 in Clinical Global Impression of Severity (CGI-S), and 2) change from baseline to week 12 in Patient Global Impression of Severity (PGI-S).

[0051] Secondary objectives of the study include evaluating the efficacy of Compound A administered once daily for 12 weeks at doses of 0.3 mg and 4 mg compared to placebo on functional outcomes and patient-reported symptoms in adults with PTSD. Evaluand variables are: 1) Responder analysis defined in three separate ways: i) percentage of participants with ≥ 30% improvement in CAPS-5 total symptom severity score from baseline to week 12, ii) percentage of participants with very large or large improvement in CGI-C at weeks 4 and 12, and iii) percentage of participants with ≥ 1 unit improvement in PGI-S from baseline to week 12; 2) change in CAPS-5 total symptom severity score from baseline to week 4; and 3) change in functional outcomes measured by Brief Inventory of Psychosocial Functioning (B-IPF) and Sheehan Disability Scale (SDS) from baseline to week 12. 4) Change in patient- and clinician-reported symptoms of PTSD as assessed by the PTSD Checklist (PCL-5), PGI-S, and CGI-S from baseline to weeks 1, 4, 8, and 12. 5) Change in self-reported sleep problems as measured by the Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI-A) from baseline to week 12. 6) Change in PTSD symptom clusters (reexperiencing, avoidance, arousal, and mood) as assessed by change in subscales of the CAPS-5 from baseline to week 12. 7) Change in mood and anxiety as assessed by the Patient Health Questionnaire (PHQ-9) and Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) from baseline to weeks 4, 8, and 12. 8) Change in quality of life as measured by the Recovering Quality of Life (ReQoL) from baseline to week 12.

[0052] Secondary objectives of this study also include evaluating the efficacy of Compound A administered once daily at doses of 0.3 mg and 4 mg over 12 weeks compared to placebo on functional outcomes and patient-reported symptoms in adults with PTSD. Safety of Compound A will be assessed by the following assessments: AEs, vital signs, physical examination, 12-lead ECG, clinical laboratory tests (chemistry, hematology, urinalysis), Columbia Suicide Severity Rating Scale (C-SSRS), and withdrawal measures (Marijuana Withdrawal Checklist).

[0053] Secondary objectives of the study further include characterizing the PK and PD of Compound A in adults with PTSD using population PK modeling and simulation methodologies, as assessed by plasma concentrations of AEA, Compound A and its metabolites.

[0054] A preliminary objective is to evaluate the association between natural genetic variation in selected genes on clinical endpoints and / or incidence of AEs. Blood samples will be collected at baseline for genotyping of single nucleotide polymorphisms (SNPs) relevant to Compound A pharmacology (e.g., FAAH and CNR1), as well as preliminary SNPs related to the clinical conditions under study. Pharmacogenomic analysis via whole exome sequencing may be performed at the end of the study.

[0055] Pharmacokinetics Blood samples for measurement of plasma concentrations of Compound A and its metabolites will be collected at weeks 1, 8, and 12. A 4 mL blood sample will be collected pre-dose and one sample will be collected 2 hours (±15 minutes) post-dose at weeks 1 and 12, and 5 hours (±15 minutes) and 8 hours (±15 minutes) post-dose at week 8. The post-dose sample at week 12 should be collected after completion of the CAPS-5 assessment. Serial blood samples will be collected within 5 minutes of the nominal time post-dose.

[0056] Pharmacogenomics A 10 mL blood sample for DNA isolation will be collected from participants who consent to participate in the genetic analysis component of the study on Day 1 (eg, baseline and randomization).

[0057] Biomarkers Approximately 4 mL blood samples will be collected to investigate relevant PD biomarkers (e.g., plasma AEA concentrations, FAAH activity) at day 1, week 1, week 8, week 12, and 14 days after the last dose.

[0058] Other embodiments The above describes certain non-limiting embodiments of the present disclosure. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. 1. An oral formulation for use in a method of treating post-traumatic stress disorder (PTSD) in an individual in need of such treatment, the method comprising administering to the individual the oral formulation once daily (QD) for a period of at least 8 weeks, the oral formulation comprising 0.3 mg to 4 mg of a compound having the following structure, or a pharma- ceutical acceptable salt thereof: 【Chemistry 1】 13. An oral formulation comprising:

2. The oral formulation of claim 1, comprising 0.3 mg of the compound, or a pharma- ceutically acceptable salt thereof.

3. The oral formulation of claim 1, comprising 4 mg of the compound, or a pharma- ceutically acceptable salt thereof.

4. 2. The oral formulation of claim 1, wherein the period is at least 12 weeks.

5. The oral formulation of claim 1, administered to the individual in an amount effective to achieve a plasma concentration of the compound or a pharma- ceutically acceptable salt thereof of 1 ng / ml to 3 ng / ml.

6. The oral formulation of claim 1, administered to the individual in an amount effective to maintain a plasma concentration of the compound or a pharma- ceutically acceptable salt thereof of at least 1 ng / ml for at least 12 hours.

7. The oral formulation of claim 1, administered to the individual in an amount effective to achieve a plasma concentration of the endocannabinoid anandamide (AEA) of between 2 ng / ml and 5 ng / ml.

8. The oral formulation of claim 1, administered to the individual in an amount effective to maintain a plasma concentration of the endocannabinoid anandamide (AEA) of at least 2 ng / ml for at least 12 hours.

9. The oral formulation of claim 1 , wherein the individual in need of treatment is an adult.

10. 10. The oral formulation of claim 1, wherein the individual in need of treatment has a genetic predisposition to PTSD.

11. The oral formulation of claim 1, wherein the individual in need of treatment does not have a co-occurring diagnosis of major depressive disorder.

12. The oral formulation of claim 1, wherein the individual in need of treatment is not concurrently receiving treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI).

13. The oral formulation of claim 1, administered to the individual as a monotherapy.

14. The oral formulation of claim 1, wherein the individual in need of treatment is an adult male.

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