Neurobehavioral Disinhibition
Conditions
Keywords
aggression, agitation, irritability, non-penetrating brain injury, traumatic brain injury, TBI, AVP-786
Brief summary
This is a multicenter, randomized, placebo-controlled study to evaluate AVP-786 for the treatment of neurobehavioral disinhibition including aggression, agitation, and irritability in participants with traumatic brain injury (TBI).
Detailed description
Eligible participants for this study must have a diagnosis of neurobehavioral disinhibition including aggression, agitation, and irritability that persists after brain injury. This is a multicenter, randomized, placebo-controlled study, consisting of up to 12 weeks of treatment.
Interventions
DRUGPlacebo
Administered as capsules
DRUGAVP-786-28
28 mg of d6-DM and 4.9 mg of Q
DRUGAVP-786-42.63
42.63 mg of d6-DM and 4.9 mg of Q
Sponsors
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants with TBI * Participants with neurobehavioral disinhibition symptoms that are present after trauma or after recovery of consciousness * Score of ≥4 on the mCGI-S scale and the Agitation/Aggression or Irritability/Lability subscales of the Neuropsychiatric Inventory (NPI) scale at screening and baseline * Participants with a reliable caregiver
Exclusion criteria
* Participants with significant symptoms of a major depressive disorder * Participants with a history of or current clinical symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, antisocial personality disorder, or borderline personality disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the Neuropsychiatric Inventory Clinician Rating Scale (NPI-C) Subscale of Aggression, Agitation, and Irritability/Lability (NPI-C-3) | Baseline to Week 6 | NPI-C is a retrospective informant/caregiver interview covering 12 neuropsychiatric symptom domains. These are collectively rated first by the informant/caregiver based on frequency (0-4);severity (0-3);informant/caregiver distress (0-5) & then by the participant based on frequency (0-4), which the clinician then integrates into a (0-3) clinical impression severity rating. NPI-C-3= aggression, agitation, & irritability/lability subscales. NPI-C agitation domain= sum of clinical impression severity scores for agitation questions 1-13 (score=0-39). NPI-C aggression domain= sum of clinician impression severity scores for aggression questions 1-8 (score=0-24). NPI-C irritability/lability domain= sum of clinician impression severity scores for irritability/lability questions 1-12 (score=0-36). NPI-C-3 composite score ranges from 0-99. Higher score= increased severity. Least square (LS) mean was analyzed using mixed effects model repeated measures (MMRM) analysis. |
| Stage 2: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the NPI-C Subscale of NPI-C-3 | Week 7 to Week 12 | NPI-C is a retrospective informant/caregiver interview covering 12 neuropsychiatric symptom domains. These domains are collectively rated by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by participant based on frequency (0-4), which is integrated by clinician into (0-3) clinical impression severity rating. NPI-C-3=aggression, agitation, & irritability/lability subscales. NPI-C agitation domain=sum of clinical impression severity scores for agitation questions 1-13 (score=0-39). NPI-C aggression domain=sum of clinician impression severity scores for aggression questions 1-8 (score=0-24). NPI-C irritability/lability domain=sum of clinician impression severity scores for irritability/lability questions 1-12 (score= 0-36). NPI-C-3 composite score ranges from 0-99. Higher score=increased severity. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Irritability/Lability | Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12 | NPI-C is used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0 to 4), which the clinician then integrates into a (0-3) clinical impression severity rating. NPI-C irritability/lability domain score=sum of clinician impression severity scores for irritability/lability questions 1-12, score ranges from 0-36, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis. Number analyzed=number of participants with data available for analysis at the specified time point. |
| Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Disinhibition | Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12 | The NPI-C is used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0-4), which the clinician then integrates into a (0-3) clinical impression severity rating. The NPI-C disinhibition domain score is the sum of clinical impression severity scores for disinhibition questions 1-16, score ranges from 0-48, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis. Number analyzed=number of participants with data available for analysis at the specified time point. |
| Stage 1 and Stage 2: Change From Baseline in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores | Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12 | mCGI-S is 7-point (1-7) scale requiring clinician to rate severity of participant's neurobehavioral disinhibition including aggression, agitation and irritability after NPI-C interview, at time of assessment relative to clinician's past experience with participants having same diagnosis. Considering total clinical experience, participant is assessed on severity of illness at time of rating as:0: not assessed;1: normal, not at all ill;2: borderline ill;3: mildly ill;4: moderately ill;5: markedly ill;6: severely ill;7: among most extremely ill participants. Higher score=increased severity. Negative change from baseline=improvement.LS mean was analyzed using analysis of covariance (ANCOVA) model. Overall number analyzed=participants with data available for analysis. Number analyzed=participants with data available for analysis at specified time point. |
| Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Aggression | Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12 | The NPI-C was used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0-4), which the clinician then integrates into a (0-3) clinical impression severity rating. The NPI-C aggression domain score is the sum of clinician impression severity scores for aggression questions 1-8, score ranges from 0-24, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed= number of participants with data available for analysis. Number analyzed= number of participants with data available for analysis at the specified time point. |
| Stage 1 and Stage 2: Modified Clinical Global Impression of Change (mCGI-C) Raw Scores | Stage 1: Week 6; Stage 2: Week 12 | The mGCI-C is a scale that requires the clinician to rate the change of the participant's neurobehavioral disinhibition including aggression, agitation, and irritability at the time of assessment after the NPI-C interview, relative to the clinician's past experience with the participant's neurobehavioral disinhibition at admission. Considering total clinical experience, a participant is assessed for change of mental illness as: 0: not assessed; 1: very much improved; 2: much improved; 3: minimally improved; 4: no change; 5: minimally worse; 6: much worse; 7: very much worse. A higher score represents worsening of symptoms. Negative change from baseline indicates improvement. |
| Stage 1 and Stage 2: Patient Global Impression of Change (PGI-C) Raw Scores | Stage 1: Week 6; Stage 2: Week 12 | The PGI-C is a 7-point (1-7) scale used to assess treatment response, and it is rated as: 1: very much improved; 2: much improved; 3: minimally improved; 4: no change; 5: minimally worse; 6: much worse; 7: very much worse. A higher score indicates worsening of the symptoms. Negative change from baseline indicates improvement. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point. |
| Stage 1 and Stage 2: Change From Baseline in Patient Global Impression of Severity (PGI-S) Scores | Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12 | The PGI-S is a single-question scale used to assess the severity of symptoms of neurobehavioral disinhibition including aggression, agitation, and irritability, on a 7-point scale, as 1: normal, not at all ill; 2: borderline ill; 3: mildly ill; 4: moderately ill; 5: markedly ill; 6: severely ill; or 7: extremely ill. A higher score indicates worsening of the symptoms. Negative change from baseline indicates improvement. LS mean was analyzed using ANCOVA model. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point. |
| Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Agitation | Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12 | The NPI-C is used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0 to 4), which the clinician then integrates into a (0-3) clinical impression severity rating. The NPI-C agitation domain score is the sum of clinician impression severity scores for agitation questions 1-13, score ranges from 0-39, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis. Number analyzed=number of participants with data available for analysis at the specified time point. |
Countries
United States
Participant flow
Recruitment details
Participants took part in this study at 67 investigative sites in the United States from 30 May 2017 to 31 August 2022. A total of 467 participants were screened of which 168 participants were randomized to receive placebo or AVP-786.
Pre-assignment details
Study was conducted in 2 Stages. Participants randomized to receive placebo in Stage 1 were re-randomized after Week 6 to receive either placebo or AVP-786 in Stage 2. As pre-specified in protocol, participants randomized to 'AVP-786' arm were not re-randomized after Week 6 and continued receiving AVP-786 in the same arm throughout 12 weeks of study. Study is presented in 3 stages: Overall Study, Stage 1 & Stage 2.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study: Placebo Participants received AVP-786 matching placebo capsules, orally, BID during Weeks 1 to 6 of the Stage 1 treatment period. After Week 6 participants were classified as responders or non-responders and were re-randomized to receive either placebo, orally, BID or AVP-786 in a dose escalation schedule to reach the target dose of AVP-786-42.63/4.9, orally, BID during Week 7 to Week 12 of Stage 1 treatment period. | 83 |
| Overall Study: AVP-786 Participants received AVP-786-28/4.9 (d6-DM 28 mg/ Q 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28/4.9 capsule, orally, BID during Week 2, and AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg) capsules (target dose), orally, BID during Weeks 3 to 12 of the treatment period. | 85 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study (Baseline to Week 12) | Adverse Event | 3 | 6 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study (Baseline to Week 12) | Lost to Follow-up | 6 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study (Baseline to Week 12) | Non-compliance With Study Drug | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study (Baseline to Week 12) | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study (Baseline to Week 12) | Protocol Deviation | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study (Baseline to Week 12) | Reason not Specified | 8 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study (Baseline to Week 12) | Trial Site Terminated by Sponsor | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study (Baseline to Week 12) | Withdrawal by Subject | 4 | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 (Baseline to Week 6) | Adverse Event | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 6 |
| Stage 1 (Baseline to Week 6) | Lost to Follow-up | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 1 |
| Stage 1 (Baseline to Week 6) | Non-compliance With Study Drug | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 1 |
| Stage 1 (Baseline to Week 6) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Stage 1 (Baseline to Week 6) | Reason Not Specified | 0 | 0 | 5 | 0 | 0 | 0 | 0 | 2 |
| Stage 1 (Baseline to Week 6) | Trial Site Terminated by Sponsor | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 (Baseline to Week 6) | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 3 |
| Stage 2 (Week 7 to Week 12) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Stage 2 (Week 7 to Week 12) | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 |
| Stage 2 (Week 7 to Week 12) | Protocol Deviation | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 |
| Stage 2 (Week 7 to Week 12) | Reason Not Specified | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 |
| Stage 2 (Week 7 to Week 12) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Overall Study: Placebo | Overall Study: AVP-786 |
|---|---|---|---|
| Age, Continuous | 47.1 years STANDARD_DEVIATION 13.7 | 47.5 years STANDARD_DEVIATION 13.54 | 46.8 years STANDARD_DEVIATION 13.93 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 13 Participants | 10 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 52 Participants | 25 Participants | 27 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 116 Participants | 58 Participants | 58 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 147 Participants | 68 Participants | 79 Participants |
| Sex: Female, Male Female | 54 Participants | 27 Participants | 27 Participants |
| Sex: Female, Male Male | 114 Participants | 56 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 83 | 0 / 115 |
| other Total, other adverse events | 4 / 83 | 7 / 115 |
| serious Total, serious adverse events | 0 / 83 | 3 / 115 |
Outcome results
Primary
Stage 1: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the Neuropsychiatric Inventory Clinician Rating Scale (NPI-C) Subscale of Aggression, Agitation, and Irritability/Lability (NPI-C-3)
NPI-C is a retrospective informant/caregiver interview covering 12 neuropsychiatric symptom domains. These are collectively rated first by the informant/caregiver based on frequency (0-4);severity (0-3);informant/caregiver distress (0-5) & then by the participant based on frequency (0-4), which the clinician then integrates into a (0-3) clinical impression severity rating. NPI-C-3= aggression, agitation, & irritability/lability subscales. NPI-C agitation domain= sum of clinical impression severity scores for agitation questions 1-13 (score=0-39). NPI-C aggression domain= sum of clinician impression severity scores for aggression questions 1-8 (score=0-24). NPI-C irritability/lability domain= sum of clinician impression severity scores for irritability/lability questions 1-12 (score=0-36). NPI-C-3 composite score ranges from 0-99. Higher score= increased severity. Least square (LS) mean was analyzed using mixed effects model repeated measures (MMRM) analysis.
Time frame: Baseline to Week 6
Population: Modified intent-to-treat (mITT) population. Stage 1: Participants randomized in Stage 1 who took at least 1 dose of study medication \& had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1. Overall number analyzed=participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Placebo | Stage 1: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the Neuropsychiatric Inventory Clinician Rating Scale (NPI-C) Subscale of Aggression, Agitation, and Irritability/Lability (NPI-C-3) | -18.7 score on a scale | Standard Error 1.74 |
| Stage 1: AVP-786 | Stage 1: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the Neuropsychiatric Inventory Clinician Rating Scale (NPI-C) Subscale of Aggression, Agitation, and Irritability/Lability (NPI-C-3) | -20.4 score on a scale | Standard Error 1.73 |
Comparison: Treatment differences in each stage were estimated by the Mixed Model Repeated Measures (MMRM).p-value: 0.40595% CI: [-5.8, 2.4]MMRM
Primary
Stage 2: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the NPI-C Subscale of NPI-C-3
NPI-C is a retrospective informant/caregiver interview covering 12 neuropsychiatric symptom domains. These domains are collectively rated by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by participant based on frequency (0-4), which is integrated by clinician into (0-3) clinical impression severity rating. NPI-C-3=aggression, agitation, & irritability/lability subscales. NPI-C agitation domain=sum of clinical impression severity scores for agitation questions 1-13 (score=0-39). NPI-C aggression domain=sum of clinician impression severity scores for aggression questions 1-8 (score=0-24). NPI-C irritability/lability domain=sum of clinician impression severity scores for irritability/lability questions 1-12 (score= 0-36). NPI-C-3 composite score ranges from 0-99. Higher score=increased severity. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis.
Time frame: Week 7 to Week 12
Population: mITT population. Stage 2: participants randomized into Stage 2 with at least 1 NPI-C-3 efficacy assessment in Stage 2. As pre-specified in protocol, data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Placebo | Stage 2: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the NPI-C Subscale of NPI-C-3 | -5.2 score on a scale | Standard Error 4.97 |
| Stage 1: AVP-786 | Stage 2: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the NPI-C Subscale of NPI-C-3 | -5.9 score on a scale | Standard Error 5.28 |
Comparison: Treatment differences in each stage were estimated by the MMRM.p-value: 0.92195% CI: [-15.3, 13.9]MMRM
Secondary
Stage 1 and Stage 2: Change From Baseline in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores
mCGI-S is 7-point (1-7) scale requiring clinician to rate severity of participant's neurobehavioral disinhibition including aggression, agitation and irritability after NPI-C interview, at time of assessment relative to clinician's past experience with participants having same diagnosis. Considering total clinical experience, participant is assessed on severity of illness at time of rating as:0: not assessed;1: normal, not at all ill;2: borderline ill;3: mildly ill;4: moderately ill;5: markedly ill;6: severely ill;7: among most extremely ill participants. Higher score=increased severity. Negative change from baseline=improvement.LS mean was analyzed using analysis of covariance (ANCOVA) model. Overall number analyzed=participants with data available for analysis. Number analyzed=participants with data available for analysis at specified time point.
Time frame: Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Change From Baseline in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores | Change from Baseline to Week 6 | -1.2 score on a scale | Standard Error 0.16 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Change From Baseline in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores | Change from Baseline to Week 6 | -1.3 score on a scale | Standard Error 0.16 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Change From Baseline in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores | Change from Week 7 to Week 12 | -0.5 score on a scale | Standard Error 0.36 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Change From Baseline in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores | Change from Week 7 to Week 12 | -1.1 score on a scale | Standard Error 0.37 |
Comparison: Baseline to Week 6p-value: 0.66495% CI: [-0.5, 0.3]ANCOVA
Comparison: Week 7 to Week 12p-value: 0.27395% CI: [-1.9, 0.6]ANCOVA
Secondary
Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Aggression
The NPI-C was used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0-4), which the clinician then integrates into a (0-3) clinical impression severity rating. The NPI-C aggression domain score is the sum of clinician impression severity scores for aggression questions 1-8, score ranges from 0-24, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed= number of participants with data available for analysis. Number analyzed= number of participants with data available for analysis at the specified time point.
Time frame: Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Aggression | Change from Baseline to Week 6 | -3.6 score on a scale | Standard Error 0.4 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Aggression | Change from Baseline to Week 6 | -4.3 score on a scale | Standard Error 0.4 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Aggression | Change from Week 7 to Week 12 | -0.8 score on a scale | Standard Error 1.39 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Aggression | Change from Week 7 to Week 12 | -0.6 score on a scale | Standard Error 1.55 |
Comparison: Baseline to Week 6: Treatment differences in each stage were estimated by the MMRM.p-value: 0.1595% CI: [-1.7, 0.3]MMRM
Comparison: Week 7 to Week 12: Treatment differences in each stage were estimated by the MMRM.p-value: 0.92195% CI: [-4.3, 4.7]MMRM
Secondary
Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Agitation
The NPI-C is used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0 to 4), which the clinician then integrates into a (0-3) clinical impression severity rating. The NPI-C agitation domain score is the sum of clinician impression severity scores for agitation questions 1-13, score ranges from 0-39, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis. Number analyzed=number of participants with data available for analysis at the specified time point.
Time frame: Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Agitation | Change from Baseline to Week 6 | -7.0 score on a scale | Standard Error 0.69 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Agitation | Change from Baseline to Week 6 | -6.7 score on a scale | Standard Error 0.67 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Agitation | Change from Week 7 to Week 12 | -2.6 score on a scale | Standard Error 1.95 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Agitation | Change from Week 7 to Week 12 | -0.6 score on a scale | Standard Error 2.02 |
Comparison: Baseline to Week 6: Treatment differences in each stage were estimated by the MMRM.p-value: 0.70295% CI: [-1.3, 1.9]MMRM
Comparison: Week 7 to Week 12: Treatment differences in each stage were estimated by the MMRM.p-value: 0.46995% CI: [-3.6, 7.6]MMRM
Secondary
Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Disinhibition
The NPI-C is used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0-4), which the clinician then integrates into a (0-3) clinical impression severity rating. The NPI-C disinhibition domain score is the sum of clinical impression severity scores for disinhibition questions 1-16, score ranges from 0-48, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis. Number analyzed=number of participants with data available for analysis at the specified time point.
Time frame: Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Disinhibition | Change from Baseline to Week 6 | -5.1 score on a scale | Standard Error 0.82 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Disinhibition | Change from Baseline to Week 6 | -5.4 score on a scale | Standard Error 0.87 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Disinhibition | Change from Week 7 to Week 12 | -3.6 score on a scale | Standard Error 1.35 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Disinhibition | Change from Week 7 to Week 12 | -2.4 score on a scale | Standard Error 1.37 |
Comparison: Baseline to Week 6: Treatment differences in each stage were estimated by the MMRM.p-value: 0.74395% CI: [-2.4, 1.7]MMRM
Comparison: Week 7 to Week 12: Treatment differences in each stage were estimated by the MMRM.p-value: 0.57595% CI: [-3.8, 6.1]MMRM
Secondary
Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Irritability/Lability
NPI-C is used to rate the presence of neuropsychiatric symptoms across 12 domains. The 12 domains are collectively rated first by the informant/caregiver based on frequency (0-4), severity (0-3) & informant/caregiver distress (0-5), then by the participant based on frequency (0 to 4), which the clinician then integrates into a (0-3) clinical impression severity rating. NPI-C irritability/lability domain score=sum of clinician impression severity scores for irritability/lability questions 1-12, score ranges from 0-36, where higher score indicates greater clinical severity of symptom. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis. Number analyzed=number of participants with data available for analysis at the specified time point.
Time frame: Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Irritability/Lability | Change from Baseline to Week 6 | -8.5 score on a scale | Standard Error 0.94 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Irritability/Lability | Change from Baseline to Week 6 | -9.7 score on a scale | Standard Error 0.95 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Irritability/Lability | Change from Week 7 to Week 12 | -3.1 score on a scale | Standard Error 2.13 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Irritability/Lability | Change from Week 7 to Week 12 | -4.7 score on a scale | Standard Error 2.3 |
Comparison: Baseline to Week 6: Treatment differences in each stage were estimated by the MMRM.p-value: 0.26795% CI: [-3.5, 1]MMRM
Comparison: Week 7 to Week 12: Treatment differences in each stage were estimated by the MMRM.p-value: 0.60995% CI: [-8, 4.8]MMRM
Secondary
Stage 1 and Stage 2: Change From Baseline in Patient Global Impression of Severity (PGI-S) Scores
The PGI-S is a single-question scale used to assess the severity of symptoms of neurobehavioral disinhibition including aggression, agitation, and irritability, on a 7-point scale, as 1: normal, not at all ill; 2: borderline ill; 3: mildly ill; 4: moderately ill; 5: markedly ill; 6: severely ill; or 7: extremely ill. A higher score indicates worsening of the symptoms. Negative change from baseline indicates improvement. LS mean was analyzed using ANCOVA model. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
Time frame: Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Change From Baseline in Patient Global Impression of Severity (PGI-S) Scores | Change from Baseline to Week 6 | -1.1 score on a scale | Standard Error 0.21 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Change From Baseline in Patient Global Impression of Severity (PGI-S) Scores | Change from Baseline to Week 6 | -1.4 score on a scale | Standard Error 0.2 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Change From Baseline in Patient Global Impression of Severity (PGI-S) Scores | Change from Week 7 to Week 12 | 0.0 score on a scale | Standard Error 0.37 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Change From Baseline in Patient Global Impression of Severity (PGI-S) Scores | Change from Week 7 to Week 12 | -0.2 score on a scale | Standard Error 0.41 |
Comparison: Baseline to Week 6p-value: 0.15995% CI: [-0.9, 0.1]ANCOVA
Comparison: Week 7 to Week 12p-value: 0.74595% CI: [-1.5, 1.1]ANCOVA
Secondary
Stage 1 and Stage 2: Modified Clinical Global Impression of Change (mCGI-C) Raw Scores
The mGCI-C is a scale that requires the clinician to rate the change of the participant's neurobehavioral disinhibition including aggression, agitation, and irritability at the time of assessment after the NPI-C interview, relative to the clinician's past experience with the participant's neurobehavioral disinhibition at admission. Considering total clinical experience, a participant is assessed for change of mental illness as: 0: not assessed; 1: very much improved; 2: much improved; 3: minimally improved; 4: no change; 5: minimally worse; 6: much worse; 7: very much worse. A higher score represents worsening of symptoms. Negative change from baseline indicates improvement.
Time frame: Stage 1: Week 6; Stage 2: Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Modified Clinical Global Impression of Change (mCGI-C) Raw Scores | Week 6 | 2.7 score on a scale | Standard Deviation 0.96 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Modified Clinical Global Impression of Change (mCGI-C) Raw Scores | Week 6 | 2.5 score on a scale | Standard Deviation 0.91 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Modified Clinical Global Impression of Change (mCGI-C) Raw Scores | Week 12 | 3.0 score on a scale | Standard Deviation 0.85 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Modified Clinical Global Impression of Change (mCGI-C) Raw Scores | Week 12 | 2.5 score on a scale | Standard Deviation 1.17 |
Comparison: Baseline to Week 6p-value: 0.26895% CI: [-0.5, 0.2]ANCOVA
Comparison: Week 7 to Week 12p-value: 0.14795% CI: [-1.2, 0.2]ANCOVA
Secondary
Stage 1 and Stage 2: Patient Global Impression of Change (PGI-C) Raw Scores
The PGI-C is a 7-point (1-7) scale used to assess treatment response, and it is rated as: 1: very much improved; 2: much improved; 3: minimally improved; 4: no change; 5: minimally worse; 6: much worse; 7: very much worse. A higher score indicates worsening of the symptoms. Negative change from baseline indicates improvement. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
Time frame: Stage 1: Week 6; Stage 2: Week 12
Population: mITT population. Stage 1:all participants randomized in Stage 1 who took at least 1 dose of study medication \&had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1; Stage 2:participants randomized into Stage 2 \&had at least 1 NPI-C-3 efficacy assessment in Stage 2(after Week 6). As pre-specified in protocol data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Placebo | Stage 1 and Stage 2: Patient Global Impression of Change (PGI-C) Raw Scores | Week 6 | 2.7 score on a scale | Standard Deviation 1.17 |
| Stage 1: AVP-786 | Stage 1 and Stage 2: Patient Global Impression of Change (PGI-C) Raw Scores | Week 6 | 2.4 score on a scale | Standard Deviation 0.92 |
| Stage 1: Placebo Non-responders; to Stage 2: Placebo | Stage 1 and Stage 2: Patient Global Impression of Change (PGI-C) Raw Scores | Week 12 | 2.9 score on a scale | Standard Deviation 1.03 |
| Stage 1: Placebo Non-responders to Stage 2: AVP-786 | Stage 1 and Stage 2: Patient Global Impression of Change (PGI-C) Raw Scores | Week 12 | 2.6 score on a scale | Standard Deviation 1.08 |
Comparison: Baseline to Week 6p-value: 0.65595% CI: [-0.5, 0.3]ANCOVA
Comparison: Week 7 to Week 12p-value: 0.73495% CI: [-1.2, 0.9]ANCOVA