Efficacy, Safety and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

The intent of the ADCS version of the CGIC is to provide a means to reliably assess the global impression of change from Baseline in a clinical trial. The mADCS-CGIC is a modification of the ADCS-CGIC instrument that focuses specifically on agitation. The participants are asked to rate their impression of change from Baseline as: 1, marked improvement; 2, moderate improvement; 3, minimal improvement; 4, no change; 5, minimal worsening; 6, moderate worsening; 7, marked worsening. Baseline was defined as the last non-missing assessment prior to Stage 1 randomization. Treatment effects were estimated at each stage by analysis of covariance (ANCOVA) with fixed effects for treatment, Baseline CMAI Total score, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus [vs] > 6), risk assessments for falls (normal/mild vs moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by last observation carried forward (LOCF) within each stage.

The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and caregiver distress. The Agitation/Aggression domain is designed to collect information on the behavioral aspects of agitation/aggression in participants with probable Alzheimer's Disease (AD) and clinically meaningful agitation secondary to AD. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, severe. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate caregiver distress. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, marked severe. The total caregiver distress score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate aberrant motor behavior. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, severe. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening of the symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

The ZBI is a 22-item scale used to assess the impact of a participant with dementia and also other illnesses on the caregiver's burden. For each item of the scale, the caregiver indicates how often they feel the burden (never, rarely, sometimes, quite frequently, or nearly always). The score ranges from 0 to 88 and is determined by adding the numbered responses of the individual items. Higher scores indicate greater caregiver distress. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes versus no). Missing values were imputed by LOCF within each stage.

The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains, including the irritability/lability domain score. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, severe. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening of the symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

NPI evaluates both frequency and severity of 12 neuropsychiatric disturbances including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, as well as appetite/eating. Total domain score= frequency x severity and thus ranges from 1 to 12. NPI domain is rated by caregiver for symptom frequency and severity. Frequency is rated as: 1=occasionally, 2=often, 3= frequently, and 4=very frequently. Severity is rated as: 1=mild; 2= moderate, and 3=severe. Frequency and severity rating scales has defined anchor points to enhance reliability of caregiver responses. Caregiver distress is rated for each positive neuropsychiatric symptom using following anchored scores. It is rated as 0=not at all, 1=minimal, 3=moderate, 4=severe, 5=very severe. Total score is calculated by adding the individual Item scores, to yield a possible total scores of 0 to 144.

The CGIS-Agitation is an observer-rated scale that measures illness severity. CGIS is used to assess the severity of agitation. The CGIS score is rated on a 7-point scale (1 = normal, not at all ill; 7 = among the most extremely ill participants). Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes versus no). Missing values were imputed by LOCF within each stage.

The ADCS-CGIC rating scale provides a reliable means to assess change from a Baseline level of global function within the time frame of the trial. ADCS-CGIC-Overall focuses on the clinician's observations of change in the participant's cognitive, functional, and behavioral performance. The ADCS-CGIC-Overall responses (1-7) are rated as: 1 = marked improvement, 2 = moderate improvement, 3 = minimal improvement, 4 = no change, 5 = minimal worsening, 6 = moderate worsening, or 7 = marked worsening. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline CMAI Total score, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes versus no). Missing values were imputed by LOCF within each stage.

The PGIC is a 7-point (1-7) scale used to assess treatment response: 1 = very much improved, = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, or 7 = very much worse. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline CMAI Total score, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by LOCF within each stage.

The DEMQOL scale is used to evaluate health-related QOL in participants with dementia and their caregivers. There are 2 versions of the DEMQOL: a 28-item version (rated by the participant); and a 31-item version (DEMQOL-proxy, rated by the caregiver). Both versions are recommended for evaluating participants (and their caregivers) with mild to moderate dementia. The DEMQOL total score ranges from 28 to 112. The DEMQOL-proxy is used for participants with severe dementia; the total score ranges from 31 to 124. For both versions, higher scores indicate greater QOL. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 vs > 6), risk assessments for falls (normal/mild vs moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by LOCF within each stage.

The CSDD scale is used to assess signs/symptoms of major depression in participants with dementia. CSDD has 19 items, and each item is rated for severity on the following scale of 0 to 2 (0 =absent, 1= mild/intermittent 2=severe). CSDD score is calculated by summing non-missing scores from each item score. The scale ranges from 0-no depression to 38 maximum depressions. Scores above 10 indicate a probable major depression, above 18 indicate a definite major depression, and below 6 as a rule are associated with the absence of significant depressive symptoms. Higher score indicated maximum depression.

The GMHR is a global clinical rating for medical health, designed to quantify in a single number (1 to 4) the severity of general comorbidity in a participant with dementia. The ratings are: 1 = poor; 2 = fair; 3 = good; 4 = excellent to very good. Data was collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.

The ADAS is designed to evaluate the cognitive and non-cognitive behavioral dysfunction characteristics of participants with AD. The cognitive subscale (ADAS-cog) consists of 11 subsets related to memory, praxis, and language. ADAS-cog scores range from 0 to 70. Higher scores indicate greater cognitive impairment. The ADAS-cog is assessed for participants with an Mini-Mental State Examination (MMSE) score of ≥10 at the Baseline Visit. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by LOCF within each stage.

RUD evaluates dementia participants utilization of formal and informal healthcare resources, including hospitalizations and doctor visits, living assistance, and time spent by nonprofessional caregivers. The RUD is administered as a semi-structured interview with the participant's primary caregiver and contains 2 sections; one focusing on caregiver impact (loss of work and leisure time incurred by caregiver) and the other focusing on the participant's use of healthcare resources. Information of caregivers who reported their responsibilities affected their work and who visited healthcare professionals from the interviews during Stage 1 is reported for this outcome measure. Data was collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.

RUD evaluates dementia participants utilization of formal and informal healthcare resources, including hospitalizations and doctor visits, living assistance, and time spent by nonprofessional caregivers. The RUD is administered as a semi-structured interview with the participant's primary caregiver and contains 2 sections; one focusing on caregiver impact (loss of work and leisure time incurred by caregiver) and the other focusing on the participant's use of healthcare resources. Information of caregivers who reported their responsibilities affected their work and who visited healthcare professionals from the interviews during Stage 2 is reported for this outcome measure. Data was collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.

RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on hours per day caregiver spent assisting participant from interviews during Stage 1 is reported for this outcome measure, where the following questions (Q), Q1= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as toilet visits, eating, dressing, grooming, walking, bathing? Q2= On typical care day during the last 30 days, how much time per day did you assist participant with tasks as (shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= On typical care day during last 30 days, how much time per day did you spend supervising (preventing dangerous events)?(Q3). Data is collected for treatment arm groups as pre-specified in protocol for this outcome measure.

RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on hours per day caregiver spent assisting participant from interviews during Stage 1 is reported for this outcome measure, where the following questions (Q), Q1= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as toilet visits, eating, dressing, grooming, walking, bathing? Q2= On typical care day during the last 30 days, how much time per day did you assist participant with tasks as (shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= On typical care day during last 30 days, how much time per day did you spend supervising (preventing dangerous events)?(Q3). Data is collected for treatment arm groups as pre-specified in protocol for this outcome measure.

RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on days caregiver spent assisting participant from interviews during Stage 1 is reported for outcome measure, where following questions (Q), Q1= During last 30 days, how many days did you spend providing these (toilet visits, eating, dressing, grooming, walking, bathing) services to participant?; Q2= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= During last 30 days, how many days did you spend providing these services (supervising) to the participant?. Data is collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.

RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on days caregiver spent assisting participant from interviews during Stage 1 is reported for outcome measure, where following questions (Q), Q1= During last 30 days, how many days did you spend providing these (toilet visits, eating, dressing, grooming, walking, bathing) services to participant?; Q2= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= During last 30 days, how many days did you spend providing these services (supervising) to the participant?. Data is collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.