Stress Disorders, Post-Traumatic
Conditions
Brief summary
To evaluate the safety, efficacy and tolerability of brexpiprazole (with placebo) as monotherapy or combination therapy with Zoloft (sertraline) in adults with PTSD.
Detailed description
This trial is designed to assess the efficacy, safety and tolerability of flexible dose brexpiprazole as monotherapy or as combination therapy with Zoloft (Sertraline) in adult participants with PTSD. This study will consist of a continuous 12-week, double-blind treatment period with a 14-day follow-up.
Interventions
DRUGBrexpiprazole
Brexpiprazole oral tablets.
DRUGSertraline
Sertraline oral capsules.
DRUGBrexpiprazole Matching Placebo
Brexpiprazole matching placebo oral tablets.
DRUGSertraline Matching Placebo
Sertraline matching placebo oral capsules.
Sponsors
H. Lundbeck A/S
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and female participants between the years of 18-65 with a diagnosis of PTSD (diagnosis can be made at screening)
Exclusion criteria
* Index trauma event \>15 years before screening * Index trauma event at age \<16 * Any traumatic event within 3 months of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinician-Administered Post-traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (CAPS-5) Total Score | Baseline, Week 12 | CAPS-5:clinician-rated, structured interview to assess PTSD diagnostic status, symptoms severity as defined by DSM-5. CAPS-5 Past Week version of scale was completed at Baseline and at all visits after Baseline. CAPS-5 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 with range 0-80. Higher scores=worse outcome. Mixed model repeated measure (MMRM) was used for analysis. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 48 investigative sites in the United States from 26 January 2017 to 12 November 2018.
Pre-assignment details
Of the 336 participants enrolled in the study, 321 participants diagnosed with post-traumatic stress disorder (PTSD) were randomized in 1:1:1:1 ratio to receive brexpiprazole monotherapy, brexpiprazole plus sertraline combination therapy, sertraline monotherapy or placebo up to Week 12.
Participants by arm
| Arm | Count |
|---|---|
| Brexpiprazole + Sertraline Participants were administered oral brexpiprazole initial dose of 0.5 mg/day plus sertraline initial dose of 50 mg/day. The dose was up titrated to brexpiprazole maximum dose of 3 mg/day and sertraline maximum dose of 200 mg/day and continued thereafter up to Week 12 based on efficacy and tolerability. No dose reductions were allowed after Week 6 and no dose increments were allowed after Week 4. Participants also received sertraline matching placebo based on dose titration/adjustment up to Week 12. | 82 |
| Brexpiprazole Participants were administered oral brexpiprazole initial dose of 0.5 mg/day The dose was up titrated to brexpiprazole maximum dose of 3 mg/day and continued thereafter up to Week 12 based on efficacy and tolerability. No dose reductions were allowed after Week 6 and no dose increments were allowed after Week 4. Participants also received sertraline matching placebo up to Week 12. | 75 |
| Sertraline Participants were administered oral sertraline initial dose of 50 mg/day. The dose was up titrated to sertraline maximum dose of 200 mg/day and continued thereafter up to Week 12 based on efficacy and tolerability. No dose reductions were allowed after Week 6 and no dose increments were allowed after Week 4. Participants also received brexpiprazole matching placebo and sertraline matching placebo based on dose titration/adjustment up to Week 12. | 81 |
| Placebo Participants received oral brexpiprazole matching placebo tablet and oral sertraline matching placebo capsules up to Week12. | 83 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 7 | 4 | 6 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 6 | 5 | 5 | 6 |
| Overall Study | Non-Compliance With Study Drug | 1 | 1 | 1 | 0 |
| Overall Study | Protocol Deviation | 0 | 1 | 0 | 0 |
| Overall Study | Reason not Specified | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal By Caregiver | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 10 | 11 | 6 |
Baseline characteristics
| Characteristic | Total | Placebo | Sertraline | Brexpiprazole + Sertraline | Brexpiprazole |
|---|---|---|---|---|---|
| Age, Continuous | 39.2 years STANDARD_DEVIATION 11.1 | 40.3 years STANDARD_DEVIATION 11 | 38.6 years STANDARD_DEVIATION 10.9 | 38.4 years STANDARD_DEVIATION 11.9 | 39.3 years STANDARD_DEVIATION 10.6 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 49 Participants | 14 Participants | 11 Participants | 13 Participants | 11 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 271 Participants | 69 Participants | 70 Participants | 68 Participants | 64 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 4 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Black or African American | 92 Participants | 26 Participants | 22 Participants | 21 Participants | 23 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 22 Participants | 8 Participants | 6 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Race White | 197 Participants | 46 Participants | 53 Participants | 55 Participants | 43 Participants |
| Region of Enrollment United States | 321 Participants | 83 Participants | 81 Participants | 82 Participants | 75 Participants |
| Sex: Female, Male Female | 199 Participants | 48 Participants | 51 Participants | 51 Participants | 49 Participants |
| Sex: Female, Male Male | 122 Participants | 35 Participants | 30 Participants | 31 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 80 | 0 / 75 | 0 / 79 | 1 / 82 |
| other Total, other adverse events | 47 / 80 | 42 / 75 | 46 / 79 | 43 / 82 |
| serious Total, serious adverse events | 2 / 80 | 1 / 75 | 0 / 79 | 4 / 82 |
Outcome results
Primary
Change From Baseline in Clinician-Administered Post-traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (CAPS-5) Total Score
CAPS-5:clinician-rated, structured interview to assess PTSD diagnostic status, symptoms severity as defined by DSM-5. CAPS-5 Past Week version of scale was completed at Baseline and at all visits after Baseline. CAPS-5 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 with range 0-80. Higher scores=worse outcome. Mixed model repeated measure (MMRM) was used for analysis.
Time frame: Baseline, Week 12
Population: ITT Sample included all participants who were randomized in the trial and took at least one dose of double-blind investigational medicinal product (IMP) and have a Baseline and at least one post Baseline evaluation for the CAPS-5 total score. Overall number of participants analyzed are the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole + Sertraline | Change From Baseline in Clinician-Administered Post-traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (CAPS-5) Total Score | -16.4 score on a scale | Standard Error 1.43 |
| Brexpiprazole | Change From Baseline in Clinician-Administered Post-traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (CAPS-5) Total Score | -12.2 score on a scale | Standard Error 1.57 |
| Sertraline | Change From Baseline in Clinician-Administered Post-traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (CAPS-5) Total Score | -11.4 score on a scale | Standard Error 1.46 |
| Placebo | Change From Baseline in Clinician-Administered Post-traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (CAPS-5) Total Score | -10.5 score on a scale | Standard Error 1.4 |
Comparison: MMRM analysis with an unstructured (UN) variance covariance structure was performed. The model included fixed class-effect terms for treatment, trial site, type of trauma (combat related Yes/No), visit week, and an interaction term of treatment by visit week and included the interaction term of baseline values of CAPS-5 total score by visit week as a covariate.p-value: =0.002195% CI: [-9.79, -2.19]Mixed Model Repeated Measures (MMRM)
Comparison: MMRM analysis with an UN variance covariance structure was performed. The model included fixed class-effect terms for treatment, trial site, type of trauma (combat related Yes/No), visit week, and an interaction term of treatment by visit week and included the interaction term of baseline values of CAPS-5 total score by visit week as a covariate.p-value: =0.386895% CI: [-5.7, 2.22]MMRM
Comparison: MMRM analysis with an UN variance covariance structure was performed. The model included fixed class-effect terms for treatment, trial site, type of trauma (combat related Yes/No), visit week, and an interaction term of treatment by visit week and included the interaction term of baseline values of CAPS-5 total score by visit week as a covariate.p-value: =0.639995% CI: [-4.74, 2.92]MMRM
Comparison: MMRM analysis with an UN variance covariance structure was performed. The model included fixed class-effect terms for treatment, trial site, type of trauma (combat related Yes/No), visit week, and an interaction term of treatment by visit week and included the interaction term of baseline values of CAPS-5 total score by visit week as a covariate.p-value: =0.010695% CI: [-8.96, -1.2]MMRM
Comparison: MMRM analysis with an UN variance covariance structure was performed. The model included fixed class-effect terms for treatment, trial site, type of trauma (combat related Yes/No), visit week, and an interaction term of treatment by visit week and included the interaction term of baseline values of CAPS-5 total score by visit week as a covariate.p-value: =0.038495% CI: [-8.26, -0.23]MMRM