Post Traumatic Stress Disorder
Conditions
Keywords
PTSD
Brief summary
This will be a 12-week, multicenter, randomized, double-blind trial evaluating the efficacy, safety, and tolerability of fixed-dose brexpiprazole + sertraline combination treatment in adult subjects with post-traumatic stress disorder.
Interventions
DRUGBrexpiprazole
3 mg pill
DRUGSertraline
150 mg pill
OTHERPlacebo
Pill
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and female outpatients 18 to 65 years of age, inclusive, at the time of informed consent. * Participants who have post-traumatic stress disorder (PTSD), diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), and confirmed by the Mini International Neuropsychiatric Interview (MINI). * Onset of symptoms meeting the DSM-5 criteria for PTSD symptoms for a minimum of 6 months prior to screening.
Exclusion criteria
* The index traumatic event that led to the development of PTSD took place \> 9 years before screening. * The index traumatic event occurred before age 16. * Participants who have experienced a traumatic event within 3 months of screening. * Participants who are receiving disability payments because of PTSD or any other psychiatric disorder; unless the disability payments will not be impacted by potential improvements demonstrated in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Score | Baseline (Week 1), Week 10 | CAPS-5 was a structured interview designed to assess PTSD diagnostic status and symptoms severity as defined by DSM-5. CAPS -5 total score was calculated by summing severity scores for 20 DSM-5 PTSD symptoms (items 1-20) from categories: Category B: Intrusion symptoms (5 items); Category C: Avoidance symptoms (2 items); Category D: Cognition and mood symptoms (7 items); Category E: Arousal and reactivity symptoms (6 items). CAPS-5 total score was imputed by adding all subscores from categories B, C, D, E. Each symptom was scored 0=Absent to 4=Extreme/incapacitating, to yield a score range of 0-80. Higher scores indicate worse outcome. Least squares (LS) mean was determined by Mixed-effect model repeated measures (MMRM) method with fixed effect of treatment, trial site, visit week, and an interaction term of treatment by visit week, and included the interaction term of baseline values by visit week as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Global Impression - Severity (CGI-S) Score | Baseline (Week 1), Week 10 | The CGI-S is a standardized, clinician-administered global rating scale that measures disease severity. To assess CGI-S, the rater or investigator answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time? Response choices include: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. The score 0 (not assessed) was to be set to missing. The CGI-S is therefore a 7-point scale from 1 through 7. A higher score on the CGI-S represents a higher severity of disease. LS mean was determined by MMRM method with fixed effect of treatment, trial site, visit week, and an interaction term of treatment by visit week, and included the interaction term of baseline values by visit week as a covariate. |
| Change in Brief Inventory of Psychosocial Functions (B-IPF) Score | Baseline, Week 12 | The B-IPF is a short patient-reported questionnaire consisting of 7 questions which measure PTSD-specific psychosocial function on a 7-point Likert scale (0 = not at all to 6 = very much, and a not applicable option) with a recall period of 30 days. The B-IPF measures the concepts of romantic relationships, parenting, family, friendships and socializing, work, education, and self-care. Total score ranges from 0-100 and is calculated by summing the completed scale items, dividing by the maximum possible score of all items and multiplying by 100. Higher scores indicate greater impairment. LS mean was determined by MMRM method with fixed effect of treatment, trial site, visit week, and an interaction term of treatment by visit week, and included the interaction term of baseline values by visit week as a covariate. |
Countries
United States
Participant flow
Recruitment details
A total of 591 participants took part in the study at 75 investigative sites in the United States from 30 October 2019 to 15 August 2023.
Pre-assignment details
Participants with a diagnosis of post-traumatic stress disorder (PTSD) were first enrolled in a 1-week placebo run-in period. At the end of placebo run-in period, participants were randomized in a 1:1:1 ratio to receive a combination of Brexpiprazole (2 \[milligrams\]mg/day) + Sertraline, Brexpiprazole (3 mg/day) + Sertraline or Sertraline + Placebo in the double-blind treatment (DBT) period.
Participants by arm
| Arm | Count |
|---|---|
| Brexpiprazole (2 mg) + Sertraline Randomized participants received brexpiprazole 2 mg, orally, QD in combination with sertraline, 150 mg, orally, QD from Week 1 to Week 12 of the DBT period. | 191 |
| Brexpiprazole (3 mg) + Sertraline Randomized participants received brexpiprazole 3 mg, orally, QD in combination with sertraline, 150 mg, orally, QD from Week 1 to Week 12 of the DBT period. | 185 |
| Sertraline + Placebo Randomized participants received sertraline 150 mg, orally, QD, in combination with sertraline matching placebo, orally, QD from Week 1 to Week 12 of the DBT period. | 177 |
| Total | 553 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double Blind Treatment Period | Adverse Event | 0 | 9 | 9 | 8 |
| Double Blind Treatment Period | Death | 0 | 1 | 0 | 0 |
| Double Blind Treatment Period | Lost to Follow-up | 0 | 22 | 11 | 25 |
| Double Blind Treatment Period | Non-Compliance With Study Drug | 0 | 4 | 4 | 2 |
| Double Blind Treatment Period | Physician Decision | 0 | 1 | 0 | 1 |
| Double Blind Treatment Period | Pregnancy | 0 | 1 | 0 | 1 |
| Double Blind Treatment Period | Protocol Deviation | 0 | 7 | 6 | 4 |
| Double Blind Treatment Period | Reason Not Specified | 0 | 1 | 3 | 6 |
| Double Blind Treatment Period | Withdrawal by Subject | 0 | 19 | 29 | 14 |
| Placebo Run-in Period | Not Randomized | 38 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Brexpiprazole (2 mg) + Sertraline | Brexpiprazole (3 mg) + Sertraline | Sertraline + Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 37.1 years STANDARD_DEVIATION 12.1 | 36.3 years STANDARD_DEVIATION 11.7 | 37.7 years STANDARD_DEVIATION 12.3 | 37.0 years STANDARD_DEVIATION 12.1 |
| Brief Inventory of Psychosocial Functions (B-IPF) Score | 63.3 score on a scale STANDARD_DEVIATION 20.1 | 62.5 score on a scale STANDARD_DEVIATION 22.4 | 59.9 score on a scale STANDARD_DEVIATION 20.5 | 61.9 score on a scale STANDARD_DEVIATION 21 |
| Clinical Global Impression - Severity (CGI-S) Score | 4.6 score on a scale STANDARD_DEVIATION 0.7 | 4.5 score on a scale STANDARD_DEVIATION 0.7 | 4.7 score on a scale STANDARD_DEVIATION 0.7 | 4.6 score on a scale STANDARD_DEVIATION 0.7 |
| Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Score | 38.8 score on a scale STANDARD_DEVIATION 8.3 | 37.8 score on a scale STANDARD_DEVIATION 7.3 | 39.3 score on a scale STANDARD_DEVIATION 7.8 | 38.7 score on a scale STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 8 Participants | 5 Participants | 19 Participants |
| Race/Ethnicity, Customized Black or African American | 46 Participants | 45 Participants | 44 Participants | 135 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 48 Participants | 37 Participants | 37 Participants | 122 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 143 Participants | 146 Participants | 140 Participants | 429 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 0 Participants | 15 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 130 Participants | 124 Participants | 121 Participants | 375 Participants |
| Sex: Female, Male Female | 142 Participants | 141 Participants | 126 Participants | 409 Participants |
| Sex: Female, Male Male | 49 Participants | 44 Participants | 51 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 185 | 0 / 180 | 0 / 172 |
| other Total, other adverse events | 31 / 185 | 35 / 180 | 36 / 172 |
| serious Total, serious adverse events | 1 / 185 | 1 / 180 | 3 / 172 |
Outcome results
Primary
Change From Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Score
CAPS-5 was a structured interview designed to assess PTSD diagnostic status and symptoms severity as defined by DSM-5. CAPS -5 total score was calculated by summing severity scores for 20 DSM-5 PTSD symptoms (items 1-20) from categories: Category B: Intrusion symptoms (5 items); Category C: Avoidance symptoms (2 items); Category D: Cognition and mood symptoms (7 items); Category E: Arousal and reactivity symptoms (6 items). CAPS-5 total score was imputed by adding all subscores from categories B, C, D, E. Each symptom was scored 0=Absent to 4=Extreme/incapacitating, to yield a score range of 0-80. Higher scores indicate worse outcome. Least squares (LS) mean was determined by Mixed-effect model repeated measures (MMRM) method with fixed effect of treatment, trial site, visit week, and an interaction term of treatment by visit week, and included the interaction term of baseline values by visit week as a covariate.
Time frame: Baseline (Week 1), Week 10
Population: FAS for Enriched participants included those participants in the Enriched Randomized Sample who received at least 1 dose of double-blind IMP, had a baseline value (Week 1) and at least 1 post baseline efficacy evaluation for CAPS-5 total score. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole (2 mg) + Sertraline | Change From Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Score | -16.53 score on a scale | Standard Error 1.19 |
| Brexpiprazole (3 mg) + Sertraline | Change From Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Score | -18.28 score on a scale | Standard Error 1.23 |
| Sertraline + Placebo | Change From Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Score | -17.57 score on a scale | Standard Error 1.19 |
p-value: 0.516595% CI: [-2.09, 4.16]MMRM
p-value: 0.659395% CI: [-3.88, 2.46]MMRM
Secondary
Change in Brief Inventory of Psychosocial Functions (B-IPF) Score
The B-IPF is a short patient-reported questionnaire consisting of 7 questions which measure PTSD-specific psychosocial function on a 7-point Likert scale (0 = not at all to 6 = very much, and a not applicable option) with a recall period of 30 days. The B-IPF measures the concepts of romantic relationships, parenting, family, friendships and socializing, work, education, and self-care. Total score ranges from 0-100 and is calculated by summing the completed scale items, dividing by the maximum possible score of all items and multiplying by 100. Higher scores indicate greater impairment. LS mean was determined by MMRM method with fixed effect of treatment, trial site, visit week, and an interaction term of treatment by visit week, and included the interaction term of baseline values by visit week as a covariate.
Time frame: Baseline, Week 12
Population: FAS for Enriched participants included those participants in the Enriched Randomized Sample who received at least 1 dose of double-blind IMP, had a baseline value (Week 1) and at least 1 post baseline efficacy evaluation for CAPS-5 total score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole (2 mg) + Sertraline | Change in Brief Inventory of Psychosocial Functions (B-IPF) Score | -27.12 score on a scale | Standard Error 2.67 |
| Brexpiprazole (3 mg) + Sertraline | Change in Brief Inventory of Psychosocial Functions (B-IPF) Score | -31.79 score on a scale | Standard Error 2.86 |
| Sertraline + Placebo | Change in Brief Inventory of Psychosocial Functions (B-IPF) Score | -22.96 score on a scale | Standard Error 2.71 |
p-value: 0.233195% CI: [-11, 2.69]MMRM
p-value: 0.013495% CI: [-15.82, -1.85]MMRM
Secondary
Change in Clinical Global Impression - Severity (CGI-S) Score
The CGI-S is a standardized, clinician-administered global rating scale that measures disease severity. To assess CGI-S, the rater or investigator answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time? Response choices include: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. The score 0 (not assessed) was to be set to missing. The CGI-S is therefore a 7-point scale from 1 through 7. A higher score on the CGI-S represents a higher severity of disease. LS mean was determined by MMRM method with fixed effect of treatment, trial site, visit week, and an interaction term of treatment by visit week, and included the interaction term of baseline values by visit week as a covariate.
Time frame: Baseline (Week 1), Week 10
Population: FAS for Enriched participants included those participants in the Enriched Randomized Sample who received at least 1 dose of double-blind IMP, had a baseline value (Week 1) and at least 1 post baseline efficacy evaluation for CAPS-5 total score. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole (2 mg) + Sertraline | Change in Clinical Global Impression - Severity (CGI-S) Score | -1.26 score on a scale | Standard Error 0.1 |
| Brexpiprazole (3 mg) + Sertraline | Change in Clinical Global Impression - Severity (CGI-S) Score | -1.31 score on a scale | Standard Error 0.11 |
| Sertraline + Placebo | Change in Clinical Global Impression - Severity (CGI-S) Score | -1.29 score on a scale | Standard Error 0.1 |
p-value: 0.821595% CI: [-0.25, 0.31]MMRM
p-value: 0.858495% CI: [-0.31, 0.26]MMRM