Post-Traumatic Stress Disorder
Conditions
Brief summary
To evaluate the safety, tolerability, and response profile of NYX-783 in a Post-Traumatic Stress Disorder population.
Detailed description
The study will be a 10 to 12-week study, including a 1 to 3-week screening Period, followed by a double-blind, randomized, placebo-controlled, parallel-group Treatment Period, and a 1-week follow-up Period. Subjects eligible for the study will be randomized to receive either NYX-783 (4-weeks) or placebo (4 or 8-weeks).
Interventions
DRUGPlacebo oral capsule
Matching placebo capsules.
DRUGNYX-783
NYX-783 is a small molecule that modulates the N-methyl-D-aspartate receptor (NMDAR).
Sponsors
Premier Research
Massachusetts General Hospital
Aptinyx
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Subjects will be randomized to receive placebo or NYX-783.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* A primary diagnosis of PTSD \[Post Traumatic Stress Disorder, according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders)\] with the primary traumatic event occurring ≥12 months prior to screening. * PCL-5 (PTSD Checklist for DSM-5) ≥38 at screening. * CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) total score ≥30 at screening.
Exclusion criteria
* Complex PTSD. * Trauma focused psychotherapies. * Primary traumatic event occurred prior to 2001. * Primary traumatic event was followed by further major traumatic life episodes. * Other psychiatric disorders that is the primary focus of treatment or followed/worsened since exposure to the trauma (except for major depressive disorder or anxiety disorders that followed exposure to the trauma or an anxiety disorder that showed a worsening after trauma) * Current use of medications with primarily central nervous system activities * Other clinically significant medical histories that may interfere with completing the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Change from baseline to week 4 (Stage 1) | CAPS-5 \[Clinician Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)\] is a structured interview for diagnosis and assessment of PTSD. The assessor combines information about frequency and intensity of an item into a severity rating (0-4). CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms. CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for symptoms corresponding to a given DSM-5 cluster: intrusions (items 1-5, minimum score 0, maximum score 20), avoidance (items 6-7, minimum score 0, maximum score 8), negative alterations in cognitions and mood (items 8-14, minimum score 0, maximum score 28), and alterations in arousal and reactivity (items 15-20, minimum score 0, maximum score 24). CAPS-5 Total Scores range from 0 to 80. A higher score corresponds to more severe PTSD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PSQI (Pittsburgh Sleep Quality Index) Global Score | Change from baseline to week 4 (Stage 1) | Assess the effects of NYX-783 compared to placebo in changes in sleep quality as measure by the PSQI Global Score. The PSQI is a questionnaire to assess sleep quality and disturbances. In scoring the PSQI, seven component scores are derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality. A score \>5 indicates significant sleep disturbance. |
| PSQI-A (Pittsburgh Sleep Quality Index-Addendum) Global Score | Change from baseline to week 4 (Stage 1) | Assess the effects of NYX-783 compared to placebo in changes in sleep quality as measure by the PSQI-A Global Score. The PSQI-A score ranges from 0-21; lower scores represent less disruptive behavior. |
| PCL-5 (PTSD-Checklist for DSM-5) | Change from baseline to week 4 (Stage 1) | Assess the effect of NYX-783 compared to placebo in changes of symptoms as measured by PCL-5. The PCL-5 ranges from 0 to 80; a higher score corresponds to more severe PTSD. |
| CGI-S (Clinical Global Impression - Severity) | Change from baseline to week 4 (Stage 1) | Assess the effect of NYX-783 compared to placebo in the change in global clinical severity of PTSD symptoms as measured by the CGI-S. The Clinical Global Impressions-Severity (CGI-S) score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill subjects). |
| HADS-A (Hospital Anxiety and Depression Scale) | From baseline to week 4 (Stage 1) | The HADS is a self-assessment tool consisting of two subscales, one for anxiety (HADS-A) and one for depression (HADS-D). Scores for items in each subscale of the HADS are summed to produce an anxiety score (HADS-A) or a Depression score (HADS-D), or can be added to produce a total score (HADS-T). Each item is rated on a 4-point scale (ranging from 0 = no not at all, to 3 = yes definitely), for a total score ranging from 0-42 and sub scores for anxiety or depression ranging from 0-21 for each subscale. Higher scores represent more severe anxiety or depression. HADS-A is presented here. |
| BAC (Brief Assessment of Cognition) Symbol Coding | Change from baseline to week 4 (Stage 1) | Assess the effect of NYX-783 compared to placebo in changes in cognitive function as measured by the BAC Symbol Coding. BAC symbol coding score is a count which ranges from 0 to 110; higher scores represent higher function. |
Countries
United States
Participant flow
Pre-assignment details
Participants were randomized to Placebo, NYX-783 50mg QD, or NYX-783 10mg QD during Stage 1. Participants were re-randomized to Placebo, NYX-783 50mg QD, or NYX-783 10mg QD in Stage 2. Participants who received Placebo in Stage 1 were classified as Responders or Non-responders in Stage 2. 160 subjects were randomized. 7 subjects received 50mg QW in a prior protocol version; they were not assigned to the Arms/Groups above. 1 subject was randomized in Stage 1 but did not receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo oral capsule: Matching placebo capsules. | 103 |
| NYX-783 High Dose (50 mg QD) NYX-783: NYX-783 is a small molecule that modulates the N-methyl-D-aspartate receptor (NMDAR). | 26 |
| NYX-783 Low Dose (10 mg QD) NYX-783: NYX-783 is a small molecule that modulates the N-methyl-D-aspartate receptor (NMDAR). | 23 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Stage 1 | Adverse Event | 3 | 3 | 1 |
| Stage 1 | Lost to Follow-up | 3 | 2 | 2 |
| Stage 1 | noncompliance, personal reason | 2 | 0 | 0 |
| Stage 1 | randomization error | 0 | 1 | 0 |
| Stage 1 | Withdrawal by Subject | 9 | 1 | 0 |
| Stage 2 | Adverse Event | 2 | 0 | 0 |
| Stage 2 | Lost to Follow-up | 3 | 2 | 1 |
| Stage 2 | protocol deviation | 1 | 0 | 0 |
| Stage 2 | Withdrawal by Subject | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | NYX-783 High Dose (50 mg QD) | NYX-783 Low Dose (10 mg QD) | Total |
|---|---|---|---|---|
| Age, Continuous | 40.8 years STANDARD_DEVIATION 11.42 | 43.8 years STANDARD_DEVIATION 12.54 | 43.7 years STANDARD_DEVIATION 11.96 | 41.8 years STANDARD_DEVIATION 11.7 |
| Baseline CAPS-5 Total Score | 40.6 units on a scale STANDARD_DEVIATION 7.58 | 36.5 units on a scale STANDARD_DEVIATION 7.37 | 38.3 units on a scale STANDARD_DEVIATION 8.26 | 39.6 units on a scale STANDARD_DEVIATION 7.76 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 6 Participants | 6 Participants | 35 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 75 Participants | 17 Participants | 15 Participants | 107 Participants |
| Region of Enrollment United States | 103 participants | 26 participants | 23 participants | 152 participants |
| Sex: Female, Male Female | 61 Participants | 15 Participants | 16 Participants | 92 Participants |
| Sex: Female, Male Male | 42 Participants | 11 Participants | 7 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 141 | 0 / 52 | 0 / 46 |
| other Total, other adverse events | 9 / 141 | 4 / 52 | 3 / 46 |
| serious Total, serious adverse events | 0 / 141 | 0 / 52 | 0 / 46 |
Outcome results
Primary
CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores
CAPS-5 \[Clinician Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)\] is a structured interview for diagnosis and assessment of PTSD. The assessor combines information about frequency and intensity of an item into a severity rating (0-4). CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms. CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for symptoms corresponding to a given DSM-5 cluster: intrusions (items 1-5, minimum score 0, maximum score 20), avoidance (items 6-7, minimum score 0, maximum score 8), negative alterations in cognitions and mood (items 8-14, minimum score 0, maximum score 28), and alterations in arousal and reactivity (items 15-20, minimum score 0, maximum score 24). CAPS-5 Total Scores range from 0 to 80. A higher score corresponds to more severe PTSD.
Time frame: Change from baseline to week 4 (Stage 1)
Population: Intent to Treat, all randomized subjects
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Cognition and Mood sub-score | -4.2 units on a scale | Standard Error 0.5 |
| Placebo | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Avoidance sub-score | -1.8 units on a scale | Standard Error 0.21 |
| Placebo | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | CAPS-5 Total Score | -13.4 units on a scale | Standard Error 1.06 |
| Placebo | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Intrusion sub-score | -4.4 units on a scale | Standard Error 0.35 |
| Placebo | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Arousal and Reactivity sub-score | -2.7 units on a scale | Standard Error 0.28 |
| NYX-783 High Dose (50 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Avoidance sub-score | -2.2 units on a scale | Standard Error 0.44 |
| NYX-783 High Dose (50 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | CAPS-5 Total Score | -15.7 units on a scale | Standard Error 2.24 |
| NYX-783 High Dose (50 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Intrusion sub-score | -4.3 units on a scale | Standard Error 0.75 |
| NYX-783 High Dose (50 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Cognition and Mood sub-score | -5.7 units on a scale | Standard Error 1.05 |
| NYX-783 High Dose (50 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Arousal and Reactivity sub-score | -4.1 units on a scale | Standard Error 0.61 |
| NYX-783 Low Dose (10 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Arousal and Reactivity sub-score | -3.5 units on a scale | Standard Error 0.59 |
| NYX-783 Low Dose (10 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Cognition and Mood sub-score | -3.4 units on a scale | Standard Error 1.04 |
| NYX-783 Low Dose (10 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | CAPS-5 Total Score | -11.6 units on a scale | Standard Error 2.19 |
| NYX-783 Low Dose (10 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Avoidance sub-score | -1.4 units on a scale | Standard Error 0.44 |
| NYX-783 Low Dose (10 mg QD) | CAPS-5 [Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition)] Total Score and Subscores | Intrusion sub-score | -3.7 units on a scale | Standard Error 0.72 |
Comparison: CAPS-5 Total Scorep-value: 0.1728t-test, 1 sided
Comparison: Cognition and Mood sub-scorep-value: 0.0962t-test, 1 sided
Comparison: Arousal and Reactivity sub-scorep-value: 0.0191t-test, 1 sided
Secondary
BAC (Brief Assessment of Cognition) Symbol Coding
Assess the effect of NYX-783 compared to placebo in changes in cognitive function as measured by the BAC Symbol Coding. BAC symbol coding score is a count which ranges from 0 to 110; higher scores represent higher function.
Time frame: Change from baseline to week 4 (Stage 1)
Population: Intent to Treat, all randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | BAC (Brief Assessment of Cognition) Symbol Coding | 3.8 units on a scale | Standard Deviation 8.07 |
| NYX-783 High Dose (50 mg QD) | BAC (Brief Assessment of Cognition) Symbol Coding | 2.9 units on a scale | Standard Deviation 9 |
| NYX-783 Low Dose (10 mg QD) | BAC (Brief Assessment of Cognition) Symbol Coding | 1.3 units on a scale | Standard Deviation 5.37 |
Secondary
CGI-S (Clinical Global Impression - Severity)
Assess the effect of NYX-783 compared to placebo in the change in global clinical severity of PTSD symptoms as measured by the CGI-S. The Clinical Global Impressions-Severity (CGI-S) score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill subjects).
Time frame: Change from baseline to week 4 (Stage 1)
Population: Intent to Treat, all randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CGI-S (Clinical Global Impression - Severity) | -1.1 units on a scale | Standard Deviation 1.09 |
| NYX-783 High Dose (50 mg QD) | CGI-S (Clinical Global Impression - Severity) | -1.2 units on a scale | Standard Deviation 1.03 |
| NYX-783 Low Dose (10 mg QD) | CGI-S (Clinical Global Impression - Severity) | -1.3 units on a scale | Standard Deviation 0.99 |
Secondary
HADS-A (Hospital Anxiety and Depression Scale)
The HADS is a self-assessment tool consisting of two subscales, one for anxiety (HADS-A) and one for depression (HADS-D). Scores for items in each subscale of the HADS are summed to produce an anxiety score (HADS-A) or a Depression score (HADS-D), or can be added to produce a total score (HADS-T). Each item is rated on a 4-point scale (ranging from 0 = no not at all, to 3 = yes definitely), for a total score ranging from 0-42 and sub scores for anxiety or depression ranging from 0-21 for each subscale. Higher scores represent more severe anxiety or depression. HADS-A is presented here.
Time frame: From baseline to week 4 (Stage 1)
Population: Intent to Treat, all randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HADS-A (Hospital Anxiety and Depression Scale) | -3.0 units on a scale | Standard Error 0.34 |
| NYX-783 High Dose (50 mg QD) | HADS-A (Hospital Anxiety and Depression Scale) | -4.4 units on a scale | Standard Error 0.72 |
| NYX-783 Low Dose (10 mg QD) | HADS-A (Hospital Anxiety and Depression Scale) | -4.2 units on a scale | Standard Error 0.7 |
p-value: 0.0452t-test, 1 sided
p-value: 0.0614t-test, 1 sided
Secondary
PCL-5 (PTSD-Checklist for DSM-5)
Assess the effect of NYX-783 compared to placebo in changes of symptoms as measured by PCL-5. The PCL-5 ranges from 0 to 80; a higher score corresponds to more severe PTSD.
Time frame: Change from baseline to week 4 (Stage 1)
Population: Intent to Treat, all randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PCL-5 (PTSD-Checklist for DSM-5) | -16.6 units on a scale | Standard Deviation 14.75 |
| NYX-783 High Dose (50 mg QD) | PCL-5 (PTSD-Checklist for DSM-5) | -19.9 units on a scale | Standard Deviation 13.58 |
| NYX-783 Low Dose (10 mg QD) | PCL-5 (PTSD-Checklist for DSM-5) | -17.0 units on a scale | Standard Deviation 16.45 |
Secondary
PSQI-A (Pittsburgh Sleep Quality Index-Addendum) Global Score
Assess the effects of NYX-783 compared to placebo in changes in sleep quality as measure by the PSQI-A Global Score. The PSQI-A score ranges from 0-21; lower scores represent less disruptive behavior.
Time frame: Change from baseline to week 4 (Stage 1)
Population: Intent to Treat, all randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PSQI-A (Pittsburgh Sleep Quality Index-Addendum) Global Score | -2.9 units on a scale | Standard Deviation 3.76 |
| NYX-783 High Dose (50 mg QD) | PSQI-A (Pittsburgh Sleep Quality Index-Addendum) Global Score | -1.9 units on a scale | Standard Deviation 2.66 |
| NYX-783 Low Dose (10 mg QD) | PSQI-A (Pittsburgh Sleep Quality Index-Addendum) Global Score | -3.1 units on a scale | Standard Deviation 4.84 |
Secondary
PSQI (Pittsburgh Sleep Quality Index) Global Score
Assess the effects of NYX-783 compared to placebo in changes in sleep quality as measure by the PSQI Global Score. The PSQI is a questionnaire to assess sleep quality and disturbances. In scoring the PSQI, seven component scores are derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality. A score \>5 indicates significant sleep disturbance.
Time frame: Change from baseline to week 4 (Stage 1)
Population: Intent to Treat, all randomized subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PSQI (Pittsburgh Sleep Quality Index) Global Score | -1.5 units on a scale | Standard Deviation 3.37 |
| NYX-783 High Dose (50 mg QD) | PSQI (Pittsburgh Sleep Quality Index) Global Score | -1.2 units on a scale | Standard Deviation 2.89 |
| NYX-783 Low Dose (10 mg QD) | PSQI (Pittsburgh Sleep Quality Index) Global Score | -1.8 units on a scale | Standard Deviation 4.04 |
Post Hoc
Responders (30% and 50% Improvement From Baseline) in CAPS-5 Total Score
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) is a 30-item structured interview for diagnosis and assessment of PTSD. A higher score corresponds to more severe PTSD.
Time frame: Baseline to Week 4 (Stage 1)
Population: Intent to Treat, subjects who completed Week 4
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Responders (30% and 50% Improvement From Baseline) in CAPS-5 Total Score | 30% decrease from baseline | 38 participants |
| Placebo | Responders (30% and 50% Improvement From Baseline) in CAPS-5 Total Score | 50% decrease from baseline | 23 participants |
| NYX-783 High Dose (50 mg QD) | Responders (30% and 50% Improvement From Baseline) in CAPS-5 Total Score | 30% decrease from baseline | 14 participants |
| NYX-783 High Dose (50 mg QD) | Responders (30% and 50% Improvement From Baseline) in CAPS-5 Total Score | 50% decrease from baseline | 9 participants |
| NYX-783 Low Dose (10 mg QD) | Responders (30% and 50% Improvement From Baseline) in CAPS-5 Total Score | 50% decrease from baseline | 6 participants |
| NYX-783 Low Dose (10 mg QD) | Responders (30% and 50% Improvement From Baseline) in CAPS-5 Total Score | 30% decrease from baseline | 9 participants |
Comparison: greater than or equal to 30% decrease from baselinep-value: 0.0182t-test, 1 sided
Comparison: greater than or equal to 50% decrease from baselinep-value: 0.0705t-test, 1 sided