Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/48—Other medical applications
  • A61B5/4806—Sleep evaluation
  • A61B5/4815—Sleep quality
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/16—Devices for psychotechnics; Testing reaction times ; Devices for evaluating the psychological state
  • A61B5/165—Evaluating the state of mind, e.g. depression, anxiety
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/48—Other medical applications
  • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
  • A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery

Definitions

• Post-traumatic stress disorder is a psychiatric disorder that may occur in people who have experienced or witnessed a traumatic event or who have been exposed to actual or threatened death, sexual violence or serious injury in one or more of the following ways: directly experiencing the traumatic event(s); witnessing, in person, the event(s) as it occurred to others; learning that the traumatic events(s) occurred to a close family member or friend; or experiencing repeated or extreme exposure to aversive details of the traumatic event (e.g., first responders collecting human remains, police officers being repeatedly exposed to details of the child abuse).
• Different types of traumatic events include natural disasters, a serious accident, a terrorist act, war/combat, and physical or sexual assault (e.g., rape).
• PTSD can occur in all people, of any ethnicity, nationality or culture, and at any age. PTSD affects approximately 3.5% of adults in the United States every year and an estimated one in eleven people will be diagnosed with PTSD in their lifetime. Women are twice as likely as men to have PTSD. Some symptoms among PTSD patients include difficulties falling asleep or staying asleep, nightmares, intrusive memories, psychological distress, physiological reactions, changes in thinking and mood, and increased alertness.
• DSM-5 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) is a diagnostic tool published by the American Psychiatric Association in 2013. DSM-5 contains descriptions, symptoms and criteria for diagnosing mental disorders. It also contains common language for clinicians to communicate about their patients to establish consistent and reliable diagnoses that can be used in the research of mental disorders. DSM-5 further provides researchers common language to study the criteria for potential future revisions and to aid in the development of medications and other interventions.
• the Clinician-Administered PTSD Scale is a semi -structured diagnostic interview that assesses essential features of PTSD as defined by the DSM-5 Diagnostic Criteria for PTSD (Weathers et al., 2017). It can also be used to assess associated features of the diagnostic syndrome (e.g., depersonalization and derealization). The interview is designed to accommodate different time spans post-trauma as the reference point for diagnosis.
• the CAPS affords the clinician flexibility to inquire about symptoms and diagnostic status over the past week, most recent month, and/or for lifetime diagnosis. Any one, or all three, of the time frames may be used depending on the nature of the task at hand.
• DSM-5 DSM-5
• PCL-5 DSM-5
• clinician-completed symptom severity intensity and/or frequency rating scale
• patient- completed symptom severity intensity and/or frequency rating scale
• 5-item CAPS DSM-5 Diagnostic Criteria Items Bl(intrusive memories), B2 (distressing dreams), B4 (psychological distress), B5 (physiological reactions) and E6 (sleep disturbance) (“5-item CAPS”), for example, as described in various embodiments of this disclosure, meets this unmet need.
• the 5-item CAPS or one or more of them provide a more sensitive and specific assessment of a clinical response (e.g., changes in sleep quality and sleep-dependent emotional memory processing) during the treatment of PTSD and its symptoms.
• a rating scale based on symptom severity is used; the symptom severity being the sum of the symptom intensity and symptom frequency for each assessment point in the rating scale.
• a method for assessing changes in sleep quality and/or sleep-dependent emotional memory processing in subjects suffering from or diagnosed with post-traumatic stress disorder (PTSD) as a consequence of an actual or potential treatment therefor the method being characterized by assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD, wherein the one or more DSM-5 Diagnostic Criteria items are Bl, B2, B4, B5 and E6.
• the changes in sleep quality and sleep-dependent emotional memory processing are assessed by assessing changes in DSM-5 Diagnostic Criteria items Bl, B2, B4, B5 and E6 (5-item CAPS).
• the mean at baseline is based on an assessment earlier in the course of treatment, whose potential efficacy in improving sleep quality and/or sleep-dependent emotional memory processing is being assessed. 10. The method according to embodiment 7, wherein the time between the baseline assessment and the treatment assessment is 12 weeks.
• assessing changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on one or more of a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), a Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), a PTSD checklist for DSM-5 (PCL-5), a clinician- completed symptom severity, intensity, and/or frequency rating scale, or a patient-completed symptom severity, intensity, and/or frequency rating scale.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a clinician-completed symptom severity, intensity, and/or frequency rating scale.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a patient-completed symptom severity, intensity, and/or frequency rating scale.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a clinician-completed symptom severity rating scale, wherein the symptom severity rating is the sum of a symptom intensity rating and a symptom frequency rating.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a patient-completed symptom severity rating scale, wherein the symptom severity rating is the sum of a symptom intensity rating and a symptom frequency rating.
• composition comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof in an amount equivalent to the amount of cyclobenzaprine delivered by about 2.8 mg cyclobenzaprine HC1 per day.
• composition comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof in an amount equivalent to the amount of cyclobenzaprine delivered by about 5.6 mg cyclobenzaprine HC1 per day.
• composition is administered in two or more doses in an amount equivalent to the amount of cyclobenzaprine delivered by two or more 2.8 mg doses of cyclobenzaprine HC1 per day.
• cyclobenzaprine HC1 is in the form of a eutectic, the eutectic being selected from the group consisting of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic, a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic, a mixture of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% P-mannitol eutectic and a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic, and a granule comprising an outer layer of a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic and an inner layer of P-mannitol
• composition further comprises a basifying agent.
• the basifying agent is selected from a group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.
• composition comprises a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic and a dipotassium hydrogen phosphate basifying agent, the composition being capable of sublingual administration.
• a method for assessing a clinical response to a pharmaceutical agent the clinical response being changes in sleep quality and/or sleep-dependent emotional memory processing in subjects suffering from or diagnosed with post-traumatic stress disorder (PTSD), the method being characterized by assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD, wherein the one or more DSM-5 Diagnostic Criteria items are Bl, B2, B4, B5 and E6.
• PTSD post-traumatic stress disorder
• the assessment further comprises assessing changes in one or more but not all of the other DSM-5 Diagnostic Criteria items for PTSD.
• assessing changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on one or more of a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), a Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), a PTSD checklist for DSM-5 (PCL-5), a clinician- completed symptom severity, intensity and/or frequency rating scale, or a patient-completed symptom severity, intensity and/or frequency rating scale.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the CAPS-5.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the CAPS-IV.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the clinician-completed symptom severity, intensity and/or frequency rating scale.
• assessing the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the patient-completed symptom severity, intensity and/or frequency rating scale.
• assessing changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a clinician-completed symptom severity rating scale, and wherein the symptom severity rating scale is the sum of an intensity rating scale and a frequency rating scale.
• assessing changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a patient-completed symptom severity rating scale, and wherein the symptom severity rating scale is the sum of an intensity rating scale and a frequency rating scale.
• cyclobenzaprine HC1 is in the form of a eutectic, the eutectic being selected from the group consisting of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic, a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic, a mixture of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% P-mannitol eutectic and a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic, and a granule comprising an outer layer of a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic and an inner layer of P-mannito
• the pharmaceutical agent further comprises a basifying agent.
• the basifying agent is selected from a group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.
• mannitol is P-mannitol or 6-mannitol.
• transmucosal administration comprises sublingual, buccal, intranasal or palatal administration.
• the pharmaceutical agent comprises a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic and a dipotassium hydrogen phosphate basifying agent, the pharmaceutical agent being capable of sublingual administration.
• Figure 1 depicts a Table showing the mean change from baseline at week 4 and week 12 of placebo and 5.6 mg Cyclobenzaprine HC1 groups using the CAPS-IV scoring method to determine total CAPS-5 score using 5-item CAPS Bl, B2, B4, B5 and E6 based on mixed model repeat measures (MMRM) of an early stop efficacy population (modified Intent to Treat population (mITT)) of P301, wherein symptom severity is the sum of intensity and frequency.
• MMRM mixed model repeat measures
• Figure 2 depicts a Table showing the mean change from baseline at week 4 and week 12 of placebo and 5.6 mg Cyclobenzaprine HC1 groups using the CAPS-IV scoring method to determine total CAPS-5 score using 5-item CAPS Bl, B2, B4, B5 and E6 based on mixed model repeat measures (MMRM) of a modified intent to treat population (mITT) population of P302, wherein symptom severity is the sum of intensity and frequency.
• MMRM mixed model repeat measures
• Figure 3 depicts a Table showing the mean change from baseline at week 4 and week 12 of placebo, 2.8 mg Cyclobenzaprine HC1, and 5.6 mg Cyclobenzaprine HC1 groups using CAPS-5 scoring method to determine total CAPS-5 score using 5-item CAPS Bl, B2, B4, B5 and E6 based on mixed model repeat measures (MMRM) of a modified intent to treat population (mITT) population of P201, wherein symptom severity is the combining of intensity and frequency.
• MMRM mixed model repeat measures
• Figure 4 depicts a Table showing the mean change from baseline at week 4 and week 12 of placebo and 5.6 mg Cyclobenzaprine HC1 groups using CAPS-5 scoring method to determine total CAPS-5 score using 5-item CAPS Bl, B2, B4, B5 and E6 based on mixed model repeat measures (MMRM) of a modified intent to treat population (mITT) population of P301, wherein symptom severity is the combining of intensity and frequency.
• MMRM mixed model repeat measures
• Figure 5 depicts a Table showing the mean change from baseline at week 4 and week 12 of placebo and 5.6 mg Cyclobenzaprine HC1 groups using CAPS-5 scoring method to determine total CAPS-5 score using 5-item CAPS Bl, B2, B4, B5 and E6 based on mixed model repeat measures (MMRM) of a modified intent to treat population (mITT) population of P302, wherein symptom severity is the combining of intensity and frequency.
• MMRM mixed model repeat measures
• the term “about” refers to a value or parameter that includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. As used herein, the term “about” permits a variation of ⁇ 10% within the range of the significant digit.
• the term “the one or more DSM-5 Diagnostic Criteria items for PTSD” refers to items Bl, B2, B4, B5 and E6 (“5-item CAPS”).
• “the one or more DSM-5 Diagnostic Criteria items for PTSD” refers to items B2 and E6.
• the one or more DSM-5 Diagnostic Criteria items for PTSD refers to items Bl, B4 and B5.
• “the one or more DSM-5 Diagnostic Criteria items for PTSD” or “the one or more 5-item CAPS” refers to any of the above.
• “the one or more DSM-5 Diagnostic Criteria items for PTSD” refers to one or more of the above but not all.
• the term “treat” and its cognates refer to a full or partial amelioration or modulation of post-traumatic stress disorder (PTSD) or at least one discernible symptom therein.
• “treat” refers to an improvement in one or both of sleep quality and sleep-dependent emotional memory processing.
• “treat” refers to consolidation of fear extinction.
• “treat” refers to a reduction of sleep disturbances.
• “treat” refers to a reduction of intrusion symptoms.
• the term “sleep-dependent emotional memory processing” refers to the effect of sleep (e.g., REM sleep and non-REM sleep) in assisting memory consolidation and conversion of short-term memory to long-term memory.
• sleep e.g., REM sleep and non-REM sleep
• “sleepdependent emotional memory processing” refers to consolidation of fear extinction in subjects suffering from or diagnosed with PTSD.
• sleep e.g., REM sleep and non-REM sleep
• “sleep-dependent emotional memory processing” refers to consolidation of fear extinction in subjects suffering from or diagnosed with PTSD.
• “sleep-dependent emotional memory processing” refers to memory consolidation in subjects suffering from or diagnosed with PTSD.
• memory consolidation refers to a time-dependent process by which recent learned experiences are converted into long-term memory.
• the term “fear extinction” refers to a decline in conditioned fear responses following nonreinforced exposure to a fear conditioned stimulus.
• the term “consolidation of fear extinction”, also known as “fear extinction consolidation”, refers to learning to reduce and/or extinguish fear to stimuli and situations that no longer predict danger so that the learned experiences are converted into longterm memory.
• clinical response refers to a change in sleep quality and/or sleep-dependent emotional memory processing as a consequence of a treatment.
• the term “mean change from baseline” refers to a difference in the mean of the total score of one of the one or more DSM-5 Diagnostic Criteria items for PTSD or a combination of them, alone or optionally together with one or more but not all of the other DSM-5 Diagnostic Criteria items for PTSD (the optional “one or more of the other DSM-5 Diagnostic Criteria items for PTSD”) during or after treatment as compared to that mean at a baseline, the baseline being from an assessment before initiation of the treatment or being from an assessment earlier in the course of the treatment.
• “mean change from baseline” refers to a primary efficacy endpoint.
• the “mean change from baseline” refers to a difference of the mean score of one of the one or more DSM-5 Diagnostic Criteria items for PTSD or a combination of more than one of the one or more of those DSM-5 Diagnostic Criteria items for PTSD and optionally the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during or after treatment as compared to that of a baseline, the baseline being from an assessment before initiation of the treatment or being from an assessment earlier in the course of the treatment.
• the term “one or more but not all of the other DSM-5 Diagnostic Criteria items for PTSD” or the optional “one or more of the other DSM-5 Diagnostic Criteria items for PTSD” refers to one or more, but not all, of the CAPS-5 items Al, A2, A3, A4, B3, Cl, C2, DI, D2, D3, D4, D5, D6, D7, El, E2, E3, E4, E5, F, G, and H.
• the term “one or more but not all of the other DSM-5 Diagnostic Criteria items for PTSD” refers to one or more, but not all, of the CAPS-5 items B3, Cl, C2, DI, D2, D3, D4, D5, D6, D7, El, E2, E3, E4, and E5.
• the optional “one or more of the other DSM-5 Diagnostic Criteria items for PTSD” refers to one or more, but not all, of the CAPS-5 items B3, Cl, C2, DI, D2, D3, D4, D5, D6, D7, El, E2, E3, E4, and E5.
• MI Multiple Imputation
• MMRM Mated-Effect Model Repeated Measure
• MMRM is an analytical method that models random-effects and fixed-effects.
• MMRM is used to assess changes in sleep quality and/or sleep-dependent emotional memory processing.
• MMRM and MI are used to assess changes in sleep quality and/or sleep-dependent emotional memory processing.
• Responder Analysis refers to an analysis of the proportion of participants who achieved a pre-defined level of improvement on one of the main outcomes at a certain time point. A subject could either have improved by a predefined level of improvement and ‘responded’ to therapy (“responder”), or not achieved the pre-defined improvement, and thus failed to respond to therapy (“non-responder”).
• CGI Clinical Global Impression
• CGI-S Clinical Global Impression-Severity
• CGI-I Clinical Global Impression- Improvement
• CGI-S scale responses include: 1) normal or not at all ill; 2) borderline mentally ill; 3) mildly ill; 4) moderately ill; 5) markedly ill; 6) severely ill; or 7) among the most extremely ill patients.
• CGI-I scale is a 7-point scale that requires the clinician to assess how much the patient’s illness has improved or worsened relative to a baseline state at the beginning of an intervention.
• CGI-I scale responses include: 1) very much improved; 2) much improved; 3) minimally improved; 4) no change; 5) minimally worse; 6) much worse; or 7) very much worse.
• PGIC Patient Global Impression of Change
• PC A Principal Component Analysis
• Network Analysis refers to statistical analysis comprising graphical representations of the relationships between variables. Relationships are referred to as “edges” and the variables are referred to as “nodes”. Relationships can be symmetrical or asymmetrical. Different types of network analysis include electric, social, biological, narrative, and link.
• RHNPCOT Randomization Honoring Nonparametric Combination of Tests
• NPCOT non-parametric combination of tests
• randomization tests refers to univariate tests, multivariate tests, and including but not limited to NPCOT to build tests from multivariate observations.
• the term “trauma” refers to one or more of the DSM-5 PTSD Diagnostic Criterion A-qualifying traumas. In some embodiments, “trauma” refers to exposure to death. In some embodiments, “trauma” refers to exposure to threatened death. In some embodiments, “trauma” refers to exposure to actual or threatened serious injury. In some embodiments, “trauma” refers to exposure to actual or threatened sexual violence.
• exposure refers to direct or indirect forms of exposure to a DSM-5 PTSD Diagnostic Criterion A-qualifying trauma.
• exposure refers to direct exposure.
• exposure refers to witnessing the trauma.
• exposure refers to learning that a relative or close friend was exposed to the trauma.
• exposure refers to repeated or extreme exposure to aversive details of the trauma.
• exposure refers to indirect exposure to aversive details of the trauma.
• the cyclobenzaprine HC1 eutectic is administered together with a basifying agent.
• a basifying agent included in some embodiments of this disclosure is selected from a group consisting of potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2HPO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (monosodium phosphate, monobasic sodium phosphate, NaPfcPC ), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, TsfeHPC ), trisodium phosphate (NasPC ), bicarbonate or carbonate salts, dipotassium phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (
• the basifying agent is potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4) or dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2HPO4).
• the basifying agent is an ingredient (and excipient) in a tablet, and the basifying agent exerts its effects during the time the tablet is being dispersed in one or more mucous membranes, while parts of the formulation are dissolving in the saliva and/or being dispersed in one or more mucous membranes and for a period of time after the tablet or parts thereof is dispersed in one or more mucous membranes.
• a basifying agent with particular effects on cyclobenzaprine HC1 is dipotassium hydrogen phosphate (K2HPO4). Another basifying agent with particular effects on cyclobenzaprine HC1 is potassium dihydrogen phosphate (KH2PO4). Another basifying agent with particular effects on cyclobenzaprine HC1 is disodium hydrogen phosphate (ISfeHPC ). Another basifying agent with particular effects on cyclobenzaprine HC1 is tripotassium citrate. Another basifying agent with particular effects on cyclobenzaprine HC1 is trisodium citrate.
• the cyclobenzaprine HC1 eutectic of this disclosure is selected from the group consisting of the one of the eutectics or granules referred to in Paragraph [0089], In some embodiments of this disclosure, the cyclobenzaprine HC1 is in the form of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic. See, e.g., WO2014/145156, incorporated herein by reference.
• a “eutectic” or “in the form of a eutectic” refers to a mixture of chemical compounds or elements that has a single chemical composition that melts at a lower temperature than its individual components.
• a composition comprising a eutectic is known as the eutectic composition and its melting temperature is known as the eutectic temperature.
• a “CAPS-5 scoring” refers to a method of scoring that combines the frequency score and intensity score to determine the severity score.
• CAPS-5 scoring refers to the rules as described in Tables 3-5.
• a “CAPS-IV scoring” refers to a method of scoring that sums the frequency score and intensity score to determine the severity score. “Sums” includes its cognates forms (i.e., “summing”).
• Effect Size refers a calculation based on the following formula: (LS Mean Diff/SE)*SQRT(1/Nl + 1/N2).
• LS Mean Diff is the least squares mean difference.
• SE refers to standard error.
• SQRT refers to square root.
• N1 refers to the total number of treatment (e.g., cyclobenzaprine HC1) subjects.
• N2 refers to the total number of placebo subjects.
• any suitable transmucosal route of administration may be employed for providing the subject with the dosage units of a pharmaceutical agent or drug as illustrated in this disclosure.
• transmucosal administration including sublingual, buccal, intranasal, palatal administration and the like, may be employed as appropriate.
• the sublingual dosage form is a tablet, a film, a liquid, powder, or a spray solution.
• the present disclosure provides a method for assessing changes in sleep quality and/or sleep-dependent emotional memory processing in subjects suffering from or diagnosed with post-traumatic stress disorder (PTSD) as a consequence of an actual or potential treatment therefor, the method being characterized by assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD, wherein the one or more DSM-5 Diagnostic Criteria items for PTSD are Bl, B2, B4, B5 and E6 .
• PTSD post-traumatic stress disorder
• changes in sleep quality and sleep-dependent emotional memory processing are assessed by assessing changes in DSM-5 PTSD Diagnostic Criteria items Bl, B2, B4, B5 and E6. In some embodiments, change in sleep quality is assessed by assessing changes in DSM-5 PTSD Diagnostic Criteria items B2 and E6. In some embodiments, change in sleep-dependent emotional memory processing is assessed by assessing changes in DSM-5 PTSD Diagnostic Criteria items Bl, B4 and B5.
• the method for assessing is characterized by assessing changes in the one or more DSM-5 Diagnostic Criteria items for PTSD (in the Embodiments of Paragraph [0049]) further comprises assessing changes in one or more but not all of the other DSM-5 Diagnostic Criteria items for PTSD, i.e., the optional “one or more of the other DSM-5 Diagnostic Criteria items for PTSD”.
• DSM-5 PTSD Diagnostic Criteria for PTSD items of Paragraph [0052], Paragraph [0053], Paragraph [0054], Paragraph [0055], Paragraph [0056], Paragraph [0059] and Paragraph [0060] refer to the DSM-5 PTSD Diagnostic Criteria items for PTSD of the embodiments of Paragraph [0048] and [0049],
• the assessment of changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on assessments before, during or after a treatment, whose efficacy or potential efficacy in improving sleep quality and/or sleepdependent emotional memory processing in PTSD is being assessed. In some embodiments, the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on assessments before a treatment, whose efficacy or potential efficacy in improving sleep quality and/or sleep-dependent emotional memory processing in PTSD is being assessed.
• the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on assessments during a treatment, whose efficacy or potential efficacy in improving sleep quality and/or sleep-dependent emotional memory processing in PTSD is being assessed. In some embodiments, the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on assessments after a treatment, whose efficacy or potential efficacy in improving sleep quality and/or sleepdependent emotional memory processing in PTSD is being assessed. In some embodiments, these assessments are had in the context of evaluating the response in a clinical trial of a given treatment.
• the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of one of the one or more DSM-5 Diagnostic Criteria items for PTSD or based on the mean of the total score of a combination of more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during or after treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment or being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of one of the one or more DSM-5 Diagnostic Criteria items for PTSD or based on the mean of the total score of a combination of more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during or after treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment or being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of one of the one or more DSM-5 Diagnostic Criteria items for PTSD or based on the mean of the total score of a combination of more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment or being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of one of the one or more DSM-5 Diagnostic Criteria items for PTSD or based on the mean of the total score of a combination of more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment.
• the assessment of the changes in the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of one of the one or more DSM-5 Diagnostic Criteria items for PTSD or based on the mean of the total score of a combination of more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during treatment as compared to that of a baseline, the baseline being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in one of the one or more DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of the one of the one or more of the DSM-5 Diagnostic Criteria items for PTSD after treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment or being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in one of the one or more DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of the one of the one or more DSM-5 Diagnostic Criteria items for PTSD after treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment.
• the assessment of the changes in one of the one or more DSM-5 Diagnostic Criteria items for PTSD is based on a difference in the mean score of the one of the one or more DSM-5 Diagnostic Criteria items for PTSD after treatment as compared to that of a baseline, the baseline being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the mean of the total score of a combination of the more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during or after treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment or being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the mean of the total score of a combination of the more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment or being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the mean of the total score of a combination of the more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment.
• the assessment of the changes in more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the mean of the total score of a combination of the more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD during treatment as compared to that of a baseline, the baseline being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the mean of the total score of a combination of the more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD after treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment or being based on an assessment earlier in the course of the treatment.
• the assessment of the changes in more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the mean of the total score of a combination of the more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD after treatment as compared to that of a baseline, the baseline being based on an assessment before initiation of the treatment.
• the assessment of the changes in more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on the mean of the total score of a combination of the more than one of the one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD after treatment as compared to that of a baseline, the baseline being based on an assessment earlier in the course of the treatment.
• the mean at baseline is based on an assessment before initiation of a treatment, whose efficacy or potential efficacy in improving sleep quality and/or sleep-dependent emotional memory processing is being assessed. In some embodiments, the mean at baseline is based on an assessment before initiation of a treatment, whose efficacy or potential efficacy in improving sleep quality is being assessed. In some embodiments, the mean at baseline is based on an assessment before initiation of a treatment, whose efficacy or potential efficacy in improving sleep-dependent emotional memory processing is being assessed
• the mean at baseline is based on an assessment before initiation of a treatment or an assessment earlier in the course of treatment, whose efficacy or potential efficacy in improving sleep quality and/or sleep-dependent emotional memory processing is being assessed. In some embodiments, the mean at baseline is based on an assessment before initiation of a treatment or an assessment earlier in the course of treatment, whose efficacy or potential efficacy in improving sleep quality is being assessed. In some embodiments, the mean at baseline is based on an assessment before initiation of a treatment or an assessment earlier in the course of treatment, whose efficacy or potential efficacy in improving sleep-dependent emotional memory processing is being assessed.
• the mean at baseline is based on an assessment earlier in the course of treatment, whose efficacy or potential efficacy in improving sleep quality and/or sleep-dependent emotional memory processing is being assessed. In some embodiments, the mean at baseline is based on an assessment earlier in the course of treatment, whose efficacy or potential efficacy in improving sleep quality is being assessed. In some embodiments, the mean at baseline is based on an assessment earlier in the course of treatment, whose efficacy or potential efficacy in improving sleep-dependent emotional memory processing is being assessed. [0066] In some embodiments, the time between the baseline assessment and the treatment assessment is 12 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 12 weeks.
• the time between the baseline assessment and the treatment assessment is at least 11 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 11 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 10 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 10 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 9 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 9 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 8 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 8 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 7 weeks.
• the time between the baseline assessment and the treatment assessment is 7 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 6 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 6 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 5 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 5 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 4 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 4 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 3 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 3 weeks.
• the time between the baseline assessment and the treatment assessment is at least 2 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 2 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 1 week. In some embodiments, the time between the baseline assessment and the treatment assessment is 1 week. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 1 month. In some embodiments, the time between the baseline assessment and the treatment assessment is 1 month. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 2 months. In some embodiments, the time between the baseline assessment and the treatment assessment is 2 months. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 3 months.
• the time between the baseline assessment and the treatment assessment is 3 months. In some embodiments, the time between the baseline assessment and the treatment assessment is 13 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 13 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 14 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 14 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 15 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 15 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 16 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 16 weeks.
• the time between the baseline assessment and the treatment assessment is 17 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 17 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 18 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 18 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 19 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 19 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is 20 weeks. In some embodiments, the time between the baseline assessment and the treatment assessment is at least 20 weeks.
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on one or more of a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), a PTSD checklist for DSM-5 (PCL-5), a clinician-completed symptom severity, intensity, and/or frequency rating scale, or a patient-completed symptom severity, intensity, and/or frequency rating scale.
• a Clinician-Administered PTSD Scale for DSM-5 CRIS-5
• PCL-5 PTSD checklist for DSM-5
• clinician-completed symptom severity, intensity, and/or frequency rating scale or a patient-completed symptom severity, intensity, and/or frequency rating scale.
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on one or more of a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), a Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), a PTSD checklist for DSM-5 (PCL-5), a clinician-completed symptom severity, intensity, and/or frequency rating scale, or a patient-completed symptom severity, intensity, and/or frequency rating scale.
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a Clinician- Administered PTSD Scale for DSM-5 (CAPS-5). In some embodiments, assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a Clinician- Administered PTSD Scale for DSM-IV (CAPS-IV).
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a PTSD checklist for DSM-5 (PCL-5). In some embodiments, assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a clinician-completed symptom severity, intensity, and/or frequency rating scale.
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a clinician-completed symptom severity rating scale, wherein the symptom severity rating is the sum of a symptom intensity rating and a symptom frequency rating. In some embodiments, assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a patient-completed symptom severity, intensity, and/or frequency rating scale.
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on a patient- completed symptom severity rating scale, wherein the symptom severity rating is the sum of a symptom intensity rating and a symptom frequency rating .
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based on CGI.
• assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD and optionally in the one or more of the other DSM-5 Diagnostic Criteria items for PTSD is based PGIC.
• the treatment reduces, modulates, ameliorates or improves at least one or a combination of the DSM-5 Diagnostic Criteria items for PTSD related to sleep disturbances and/or intrusion symptoms, wherein items B2 and E6 relate to sleep disturbances and items Bl, B4 and B5 relate to intrusion symptoms.
• the treatment reduces, modulates, ameliorates or improves at least one of the DSM-5 Diagnostic Criteria items for PTSD related to sleep disturbances (e.g., items B2 and E6).
• the treatment reduces, modulates, ameliorates or improves at least one of the DSM-5 Diagnostic Criteria items for PTSD related to intrusion symptoms (e.g., items Bl, B4 and B5).
• the treatment reduces, modulates, ameliorates or improves at least one of the DSM-5 Diagnostic Criteria items for PTSD Bl, B2, B4, B5 and E6. In some embodiments, the treatment reduces, modulates, ameliorates or improves a combination of the DSM-5 Diagnostic Criteria items for PTSD related to sleep disturbances and intrusion symptoms. In some embodiments, the treatment reduces, modulates, ameliorates or improves a combination of the DSM-5 Diagnostic Criteria items for PTSD related to sleep disturbances (e.g., items B2 and E6).
• the treatment reduces, modulates, ameliorates or improves a combination of the DSM-5 Diagnostic Criteria items for PTSD related to intrusion symptoms (e.g., items Bl, B4 and B5). In some embodiments, the treatment reduces, modulates, ameliorates or improves a combination of the DSM-5 Diagnostic Criteria items for PTSD Bl, B2, B4, B5 and E6.
• the change in sleep quality temporally precedes and/or potentially predicts subsequent changes in sleep-dependent emotional memory processing. In some embodiments, the change in sleep quality temporally precedes and potentially predicts subsequent changes in sleep-dependent emotional memory processing. In some embodiments, the change in sleep quality temporally precedes subsequent changes in sleepdependent emotional memory processing. In some embodiments, the change in sleep quality potentially predicts subsequent changes in sleep-dependent emotional memory processing.
• the sleep-dependent emotional memory processing comprises memory consolidation, fear extinction and consolidation of fear extinction. In some embodiments, the sleep-dependent emotional memory processing is memory consolidation. In some embodiments, the sleep-dependent emotional memory processing is fear extinction. In some embodiments, the sleep-dependent emotional memory processing is consolidation of fear extinction.
• the subject has experienced one or more DSM-5 PTSD Diagnostic Criterion A-qualifying traumas during military service. In some embodiments, the subject has experienced one or more DSM-5 PTSD Diagnostic Criterion A-qualifying traumas during civilian life or work. In some embodiments, the subject has experienced one or more DSM-5 PTSD Diagnostic Criterion A-qualifying traumas during law enforcement work. In some embodiments, the subject has experienced one or more DSM-5 PTSD Diagnostic Criterion A-qualifying traumas during first responder work. In some embodiments, the subject has experienced one or more DSM-5 PTSD Diagnostic Criterion A-qualifying traumas during work as a firefighter.
• the one or more DSM-5 PTSD Diagnostic Criterion A- qualifying traumas are selected from the group comprising an exposure to death, threatened death, actual or threatened serious injury, and/or actual or threatened sexual violence.
• the DSM-5 PTSD Criterion A-qualifying trauma is an exposure to death.
• the DSM-5 PTSD Criterion A-qualifying trauma is threatened death.
• the DSM-5 PTSD Criterion A-qualifying trauma is actual or threatened serious injury.
• the DSM-5 PTSD Criterion A-qualifying trauma is actual or threatened sexual violence.
• the exposure to one or more DSM-5 PTSD Criterion A- qualifying traumas is selected from the group consisting of direct exposure, witnessing the trauma, learning that a relative or close friend was exposed to the trauma, and indirect exposure to aversive details of the trauma.
• the exposure to one or more DSM-5 PTSD Criterion A-qualifying traumas is direct exposure.
• the exposure to one or more DSM-5 PTSD Criterion A-qualifying traumas is witnessing the trauma.
• the exposure to one or more DSM-5 PTSD Criterion A-qualifying traumas is learning that a relative or close friend was exposed to the trauma.
• the exposure to one or more DSM-5 PTSD Criterion A- qualifying traumas is indirect exposure to aversive details of the trauma.
• the subject is diagnosed with DSM-5-defmed PTSD and has a DSM-5 Diagnostic Criteria item score suggestive or indicative of mild PTSD, moderate PTSD, severe PTSD or extreme PTSD. In some embodiments, the subject is diagnosed with DSM-5-defmed PTSD and has a DSM-5 Diagnostic Criteria item score suggestive or indicative of mild PTSD. In some embodiments, the subject is diagnosed with DSM-5- defined PTSD and has a DSM-5 Diagnostic Criteria item score suggestive or indicative of moderate PTSD. In some embodiments, the subject is diagnosed with DSM-5-defmed PTSD and has a DSM-5 Diagnostic Criteria item score suggestive or indicative of severe PTSD.
• the subject is diagnosed with DSM-5-defmed PTSD and has a DSM-5 Diagnostic Criteria item score suggestive or indicative of extreme PTSD. In some embodiments, the subject is diagnosed with DSM-5-defmed PTSD and has a DSM-5 Diagnostic Criteria item score of at least 20. In some embodiments, the subject is diagnosed with DSM-5-defmed PTSD and has a DSM-5 Diagnostic Criteria item score of at least 29.
• the subject has a total PTSD Check List for DSM-5 (PCL-5) score suggestive or indicative of mild PTSD, moderate PTSD, severe PTSD or extreme PTSD. In some embodiments, the subject has a total PTSD Check List for DSM-5 (PCL-5) score suggestive or indicative of mild PTSD. In some embodiments, the subject has a total PTSD Check List for DSM-5 (PCL-5) score suggestive or indicative of moderate PTSD. In some embodiments, the subject has a total PTSD Check List for DSM-5 (PCL-5) score suggestive or indicative of severe PTSD. In some embodiments, the subject has a total PTSD Check List for DSM-5 (PCL-5) score suggestive or indicative of extreme PTSD.
• the DSM-5 Diagnostic Criteria for PTSD applies to adults, adolescents, and children older than 6 years.
• the DSM-5 Diagnostic Criteria (Table 1) are incorporated herein by reference (Substance Abuse and Mental Health Services Administration (SAMHSA), “Chapter 3, Understanding the Impact of Trauma”, Trauma-Informed Care in Behavioral Health Services TIP Series No.57: 59-89, 2014).
• the DSM-5 PTSD Diagnostic Criteria “5-item CAPS” were selected to serve an unmet need of a more sensitive and specific assessment to identify a clinical response, such as changes in sleep quality and/or sleep-dependent emotional memory processing in subjects diagnosed with or suffering from PTSD, who are undergoing treatment or who are participating in a clinical trial of a treatment.
• the “5-item CAPS” (Table 2) are:
• CAPS-IV scoring measures the symptom severity as the sum of the symptom intensity and symptom frequency for each assessment point.
• symptom frequency and symptom intensity are measured by the clinician or patient using the scales as described in Tables 6 and 7, respectively
• Frequency ratings are to be made on a 5-point continuum, from the lowest frequency (e.g., none of the time) to the highest (e.g., most or all of the time) (see, e.g., Table 6).
• the interviewer or patient should determine the most accurate rating along this continuum by first stating the prompt questions (e.g., Have you ever tried to stay away from activities or situations that reminded you of the event(s)? How often in this past month”), and if necessary, comparable alternatives (Z>r, stated in more colloquial terms), specific to each item.
• the next step is to give the patient response options by naming those anchor point descriptors which appear to most closely reflect the patient’s status. All prompt questions do not need to be asked if an accurate rating is obtained with the initial prompt question.
• Intensity rating which touch on both symptom intensity and degree of impairment, are also made on a 5-point scale, from the lowest intensity (e.g., absent) to the highest (e.g., extreme, incapacitating).
• the interviewer or patient should first state the prompt questions (e.g., How much effort did you make to avoid activities or situations related to the event(s)?) and appropriate follow-up questions. All attempts at behavioral avoidance should be rated, for example, a combat veteran who avoids veteran activities and war movies. If the prompt questions do not lead to a single, fitting rating, they can be followed by asking the patient to choose the most accurate rating/description among two or more possible options.
• the PTSD Checklist for DSM-5 (PCL-5) is a 20-item self-report measure that assesses the presence and severity of PTSD symptoms (Table 8). Items on the PCL-5 corresponds with DSM-5 criteria for PTSD.
• the PCL-5 has a variety of purposes, including: 1) quantifying and monitoring symptoms over time; 2) screening individuals for PTSD; and 3) assisting in making a provisional diagnosis of PTSD.
• the PCL-5 is intended to assess patient symptoms in the past week or month. Respondents are asked to rate how bothered they have been by each of the 20 items in the past month on a 5-point Likert scale ranging from 0-4 (Table 9).
• a respondent who meets a provisional diagnosis may need further assessment (e.g., CAPS- 5) to confirm the diagnosis of PTSD.
• a total score of 31-33 or higher suggests the respondent may benefit from PTSD treatment. Scores lower than 31-33 may indicate the patient either has subthreshold symptoms of PTSD or does not meet criteria for PTSD, and this information would be incorporated into treatment planning.
• the treatment is one or more of a pharmaceutical agent- assisted psychotherapy. In some embodiments, the treatment is one or more of a pharmaceutical agent-assisted psychotherapy, the treatment comprising, administering a composition comprising the pharmaceutical agent, and undergoing psychotherapy. In some embodiments, the treatment is administering a composition comprising a pharmaceutical agent. In some embodiments, the treatment is psychotherapy. In some embodiments, the treatment is a pharmaceutical agent. In some embodiments, the treatment is administering a composition comprising one or more of a pharmaceutical agent. In some embodiments, the treatment comprises administration of a composition comprising one or more of a pharmaceutical agent, a pharmaceutical agent-assisted psychotherapy, psychotherapy, or a combination thereof
• the pharmaceutical agent of this disclosure is cyclobenzaprine HC1 or a pharmaceutically acceptable salt thereof.
• the treatment comprises administration of a composition comprising cyclobenzaprine or a pharmaceutically acceptable salt thereof in an amount equivalent to the amount of cyclobenzaprine delivered by about 2.8 mg cyclobenzaprine HC1 per day.
• the treatment comprises administration of a composition comprising cyclobenzaprine or a pharmaceutically acceptable salt thereof in an amount equivalent to the amount of cyclobenzaprine delivered by about 5.6 mg cyclobenzaprine HC1 per day.
• the composition is administered in two or more doses in an amount equivalent to the amount of cyclobenzaprine delivered by two or more 2.8 mg doses of cyclobenzaprine HC1 per day.
• a composition of 5.6 mg cyclobenzaprine HC1 is administered as two 2.8 mg doses per day.
• the treatment comprises administration of a composition comprising about 2.8 mg cyclobenzaprine HC1 per day. In some embodiments, the treatment comprises administration of a composition comprising about 5.6 mg cyclobenzaprine HC1 per day. In some embodiments, the treatment comprises administration of the composition in multiple doses per day. In some embodiments, the composition comprising about 5.6 mg cyclobenzaprine HC1 is administered to two compositions, each comprising about 2.8 mg cyclobenzaprine HC1.
• the pharmaceutically acceptable salt of cyclobenzaprine is cyclobenzaprine HC1.
• the cyclobenzaprine HC1 is in the form of a eutectic. In some embodiments, the cyclobenzaprine HC1 is in the form of a eutectic, the eutectic being selected from the group consisting of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic, a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic, a mixture of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% P-mannitol eutectic and a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic, and a granule comprising an outer layer of a 65% ⁇ 2% cyclobenzaprine HC1 and
• the cyclobenzaprine HC1 eutectic is a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic. In some embodiments, the cyclobenzaprine HC1 eutectic is a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 8-mannitol eutectic.
• the cyclobenzaprine HC1 eutectic is a mixture of a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% P-mannitol eutectic and a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic.
• the cyclobenzaprine HC1 eutectic is a granule comprising an outer layer of a 65% ⁇ 2% cyclobenzaprine HC1 and 35% ⁇ 2% 6-mannitol eutectic and an inner layer of P-mannitol.
• the mannitol is P-mannitol or 6-mannitol. In some embodiments, the mannitol is P-mannitol. In some embodiments, the mannitol is 6-mannitol.
• the composition further comprises a basifying agent.
• the basifying agent is selected from a group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.
• the basifying agent is potassium dihydrogen phosphate.
• the basifying agent is potassium dihydrogen phosphate (also known as potassium phosphate dibasic). In some embodiments, the basifying agent is tripotassium phosphate. In some embodiments, the basifying agent is sodium carbonate. In some embodiments, the basifying agent is sodium bicarbonate. In some embodiments, the basifying agent is calcium carbonate. In some embodiments, the basifying agent is calcium bicarbonate. In some embodiments, the basifying agent is TRIS buffer. In some embodiments, the basifying agent is sodium dihydrogen phosphate. In some embodiments, the basifying agent is disodium hydrogen phosphate. In some embodiments, the basifying agent is trisodium phosphate.
• the composition is suitable for transmucosal administration.
• the transmucosal administration comprises sublingual, buccal, intranasal or palatal.
• the transmucosal administration is sublingual.
• the transmucosal administration is buccal.
• the transmucosal administration is intranasal.
• the transmucosal administration is palatal.
• the composition comprises a 75% ⁇ 2% cyclobenzaprine HC1 and 25% ⁇ 2% mannitol eutectic and a potassium phosphate dibasic basifying agent, the composition being capable of sublingual administration. See International Publication No. WO2013 188847, incorporated herein by reference.
• the composition is administered at bedtime.
• the present disclosure provides a method for assessing a clinical response to a treatment (e.g., pharmaceutical agent, drug-assisted psychotherapy or psychotherapy) the clinical response being changes in sleep quality and/or sleep-dependent emotional memory processing in subjects suffering from or diagnosed with post-traumatic stress disorder (PTSD), wherein the treatment (e.g., pharmaceutical agent, drug-assisted psychotherapy or psychotherapy) has improved or has the potential of improving PTSD symptoms via a mechanism of improving sleep quality and/or sleepdependent emotional memory processing, the method being characterized by assessing changes in one or more DSM-5 Diagnostic Criteria items for PTSD, wherein the one or more DSM-5 Diagnostic Criteria items are Bl, B2, B4, B5 and E6, and optionally the one or more of the other DSM-5 Diagnostic Criteria items for PTSD.
• a treatment e.g., pharmaceutical agent, drug-assisted psychotherapy or psychotherapy
• the clinical response being changes in sleep quality and/or sleep-dependent emotional memory processing in subjects suffering from or diagnosed with post-traumatic stress disorder (PTSD)
• the treatment reduces or improves at least one or a combination of the DSM-5 Diagnostic Criteria items for PTSD related to sleep disturbances and intrusion symptoms, wherein items B2 and E6 related to sleep disturbances and items Bl, B4 and B5 related to intrusion symptoms.
• the treatment e.g., pharmaceutical agent, drug-assisted psychotherapy or psychotherapy
• reduces or improves at least one or a combination of the DSM-5 Diagnostic Criteria items for PTSD related to sleep disturbances e.g., items B2 and E6.
• the treatment reduces or improves at least one or a combination of the DSM-5 Diagnostic Criteria items for PTSD related to intrusion symptoms (e.g., items Bl, B4 and B5).
• P201 Phase 2
• P301 Phase 3
• P302 Phase 3
• P201, P301 and P302 were 12-week, multicenter, randomized, double-blind, placebo-controlled, Phase 2 and 3 studies, testing the efficacy and safety of 5.6 mg cyclobenzaprine HC1 (2 x 2.8 mg tablets) for PTSD.
• Eligible male and female subjects were 18-65 years of age and had experienced DSM-5 PTSD Criterion A-qualifying trauma(s) during military service since 2001. Subjects met DSM-5-defmed PTSD by CAPS-5 and had a severity score > 29. Subjects were also free of antidepressants and free of or could be washed off of other psychotropic medications. CAPS-5 raters were MA-level or above in mental health fields who underwent rigorous CAPS-5 rater training, certification and inter-rater reliability assessments. Safety was assessed by evaluation of adverse events (AE), vital signs, weight, and ratings of mood, suicidal behaviors and morning sedation.
• AE adverse events
• the primary efficacy endpoint for each was mean change from baseline (MCFB) in total CAPS-5 score at Week 12.
• Post-hoc analyses included principal component analysis (PCA) and network analysis on the individual 5-item CAPS to illuminate underlying structures in the data, as well as relationships between items;
• PCA principal component analysis
• MCFB analysis was performed on the CAPS-5 score for the individual DSM-5 PTSD Diagnostic Criteria 5-items Bl, B2, B4, B5 and E6, and on the total score for the 5-items.
• MCFB analysis was also performed using the severity rating scale of this disclosure for the five individual DSM-5 PTSD Diagnostic Criteria items Bl, B2, B4, B5 and E6, and on the total severity score for those 5 items.
• PCA revealed similar CAPS-5 item loadings for military and civilian PTSD and network analysis showed grouping of sleep items (B2 and E6) and intrusion items (Bl, B4 and B5).
• P201 Phase 2
• P301 Phase 3
• P302 Phase 3
• P201, P301 and P302 were 12-week, multicenter, randomized, double-blind, placebo-controlled, Phase 2 and 3 studies, testing the efficacy and safety of 5.6 mg cyclobenzaprine HC1 (2 x 2.8 mg tablets) for PTSD.
• Eligible male and female subjects were 18-65 years of age and had experienced DSM-5 PTSD Criterion A-qualifying trauma(s) during military service since 2001. Subjects met DSM-5-defmed PTSD by CAPS-5 and had a severity score > 29. Subjects were also free of antidepressants and free of or could be washed off of other psychotropic medications. CAPS-5 raters were MA-level or above in mental health fields who underwent rigorous CAPS-5 rater training, certification and inter-rater reliability assessments. Safety was assessed by evaluation of adverse events (AE), vital signs, weight, and ratings of mood, suicidal behaviors and morning sedation.
• AE adverse events
• the primary efficacy endpoint for each was mean change from baseline (MCFB) in total CAPS-5 score at Weeks 4 and 12.
• Post-hoc analyses included principal component analysis (PCA) and network analysis on the individual CAPS-5 items to illuminate underlying structures in the data, as well as relationships between items.
• PCA principal component analysis
• MCFB analysis was performed on the CAPS-5 score for the five individual DSM-5 PTSD Diagnostic Criteria items Bl, B2, B4, B5 and E6 (i.e., 5-item CAPS), and on the CAPS-5 total score for the 5- items.
• MCFB analysis was also performed using the severity rating scale of this disclosure for the 5-item CAPS, and on the total severity score for those 5 items.
• the CAPS-IV scoring method was used to calculate the total CAPS-5 score and effect size for studies P301 and P302 using DSM-5 PTSD Diagnostic Criteria items Bl, B2, B4, B5 and E6 by summing the intensity and frequency scores for each of the 5 items ( Figures 1 and 2 and Tables 10 and 11).
• LS means, differences (e.g., LS mean differences), Cl’s and p-values are based on an MMRM with fixed categorical effects of treatment, site, sex, visit and treatment by visit interaction, as well as, the continuous fixed covariates of baseline score and baseline score by visit interaction. An unstructured covariance matrix was used. P values compare the change from baseline for the active group to placebo.
• the CAPS-5 scoring method was used to calculate the total CAPS-5 score and effect size for studies P201, P301 and P302 using DSM-5 PTSD Diagnostic Criteria items Bl, B2, B4, B5 and E6 by combining the intensity and frequency scores for each of the 5 items ( Figure 3-5 and Tables 12-14).
• LS means, differences (e.g., LS mean differences), Cl’s and p-values are based on an MMRM with fixed categorical effects of treatment, site, sex, visit and treatment by visit interaction, as well as, the continuous fixed covariates of baseline score and baseline score by visit interaction. An unstructured covariance matrix was used. P values compare the change from baseline for the active group to placebo.

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