Trial Outcomes & Findings for Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Agitation in Participants With Dementia of the Alzheimer's Type (NCT NCT02442778)

Last Updated: 2022-09-09

Results Overview

The CMAI was used to assess the frequency of manifestations of agitated behaviors in elderly participants. It consists of 29 agitated items rated on a 7-point scale of frequency: 1, never; 2, less than once a week; 3, once or twice a week; 4, several times a week; 5, once or twice a day; 6, several times a day; 7, several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. Negative change from baseline indicates improvement. Mixed Model Repeated Measures (MMRM) was used for the analysis.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

522 participants

Primary outcome timeframe

Baseline, Week 12

Results posted on

2022-09-09

Participant Flow

Participants took part in the study at 83 investigative sites in North America from 11 November 2015 to 09 September 2019.

A total of 925 participants were screened of which 522 participants were enrolled and 521 participants were randomized to receive placebo or AVP-786-28 or AVP-786-42.63.

Participant milestones

Participant milestones
Measure	Placebo Participants were administered AVP-786 matching placebo capsules, orally, twice daily (BID) for up to 12 weeks.	AVP-786-28 Participants were administered AVP-786-18 capsule, orally, once daily (QD) along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Overall Study STARTED	210	151	161
Overall Study Safety Population	210	151	160
Overall Study Modified Intent-to-Treat (mITT) Population	210	150	159
Overall Study COMPLETED	192	121	146
Overall Study NOT COMPLETED	18	30	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants were administered AVP-786 matching placebo capsules, orally, twice daily (BID) for up to 12 weeks.	AVP-786-28 Participants were administered AVP-786-18 capsule, orally, once daily (QD) along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Overall Study Adverse Event	2	6	6
Overall Study Death	0	2	0
Overall Study Lack of Efficacy	1	0	0
Overall Study Lost to Follow-up	1	1	1
Overall Study Non-compliance with study drug	2	0	1
Overall Study Physician Decision	1	1	1
Overall Study Protocol Deviation	3	0	1
Overall Study Study participant withdrawal by parent or guardian	3	12	2
Overall Study Withdrawal by Subject	4	4	3
Overall Study Reason not specified	1	4	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=210 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=151 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=161 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.	Total n=522 Participants Total of all reporting groups
Age, Continuous	76.7 years STANDARD_DEVIATION 8.1 • n=5 Participants	74.6 years STANDARD_DEVIATION 7.9 • n=7 Participants	74.8 years STANDARD_DEVIATION 7.3 • n=5 Participants	75.5 years STANDARD_DEVIATION 7.9 • n=4 Participants
Sex: Female, Male Female	117 Participants n=5 Participants	84 Participants n=7 Participants	96 Participants n=5 Participants	297 Participants n=4 Participants
Sex: Female, Male Male	93 Participants n=5 Participants	67 Participants n=7 Participants	65 Participants n=5 Participants	225 Participants n=4 Participants
Race/Ethnicity, Customized Race · White	196 Participants n=5 Participants	129 Participants n=7 Participants	155 Participants n=5 Participants	480 Participants n=4 Participants
Race/Ethnicity, Customized Race · Black or African American	13 Participants n=5 Participants	14 Participants n=7 Participants	6 Participants n=5 Participants	33 Participants n=4 Participants
Race/Ethnicity, Customized Race · Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · Other	0 Participants n=5 Participants	5 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	128 Participants n=5 Participants	78 Participants n=7 Participants	113 Participants n=5 Participants	319 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Not Hispanic or Latino	82 Participants n=5 Participants	73 Participants n=7 Participants	48 Participants n=5 Participants	203 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Number analysed signifies the number of participants with available data for analysis at a specific timepoint.

Outcome measures

Outcome measures
Measure	Placebo n=210 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=150 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=159 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score Baseline	73.7 score on a scale Standard Deviation 21.13	68.8 score on a scale Standard Deviation 19.39	71.3 score on a scale Standard Deviation 20.87
Change From Baseline to Week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score Change from Baseline at Week 12	-16.2 score on a scale Standard Deviation 16.97	-12.7 score on a scale Standard Deviation 16.21	-17.0 score on a scale Standard Deviation 16.12

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at specific timepoint.

The mADCS-CGIC-Agitation is a modified version of the ADCS-CGIC containing additional questions related to agitation and an assessment of the Clinician's Impression of Change focused specifically on agitation. Participants are asked to rate their impression of change as: 1=Marked Improvement; 2=Moderate Improvement; 3=Minimal Improvement; 4=No Change; 5=Minimal Worsening; 6=Moderate Worsening; 7=Marked Worsening. Higher scores indicate worsening of agitation and positive change from baseline indicates worsening. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=190 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=118 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=141 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Relative Change From Baseline to Week 12 in the Modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC)-Agitation Score	2.9 score on a scale Standard Deviation 1.18	3.1 score on a scale Standard Deviation 1.23	2.8 score on a scale Standard Deviation 1.20

SECONDARY outcome

Timeframe: Baseline, Week 12

The NPI is a retrospective caregiver-informant interview covering 12 neuropsychiatric symptom domains. The Agitation/Aggression domain is designed to collect information on the behavioral aspects of agitation/aggression in participants with probable 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. Negative change from baseline indicates improvement in symptoms. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=192 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=123 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=148 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score	-2.5 score on a scale Standard Deviation 3.17	-2.3 score on a scale Standard Deviation 3.32	-3.2 score on a scale Standard Deviation 3.32

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at a specific timepoint.

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 with a higher score indicating worsening of symptoms. Negative change from baseline indicates improvement in symptoms. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=189 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=121 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=144 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the NPI Agitation/Aggression Caregiver Distress Score	-0.8 score on a scale Standard Deviation 1.44	-0.8 score on a scale Standard Deviation 1.61	-0.8 score on a scale Standard Deviation 1.47

SECONDARY outcome

Timeframe: Baseline, Week 12

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, marked severe. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12 with a higher score indicating worsening of symptoms. Negative change from baseline indicates improvement in symptoms. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=192 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=123 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=148 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the NPI Aberrant Motor Behavior Domain Score	-1.2 score on a scale Standard Deviation 3.75	-1.2 score on a scale Standard Deviation 3.60	-1.8 score on a scale Standard Deviation 3.57

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at a specific timepoint.

The ZBI is a 22-item scale used to assess the impact of a participants' disabilities on the caregiver's life. It is designed to reflect the burden experienced by caregivers of dementia participants and can either be completed by the caregiver or administered as an interview. Each item of the scale is rated to reflect the burden using the 5-point scale: 0=Never; 1=Rarely; 2=Sometimes; 3=Quite Frequently; 4=Nearly Always. The ZBI is scored by summing the responses of the individual questions and ranges from 0 to 88. Higher scores indicate greater caregiver distress. Negative change from baseline indicates less distress. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=190 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=118 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=141 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Zarit Burden Interview (ZBI) Score	-1.77 score on a scale Standard Deviation 9.275	-1.03 score on a scale Standard Deviation 12.195	-0.23 score on a scale Standard Deviation 11.769

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at specific timepoint.

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. Negative change from baseline indicates improvement in symptoms. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=192 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=123 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=148 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the NPI Irritability/Lability Domain Score	-1.8 score on a scale Standard Deviation 3.50	-1.2 score on a scale Standard Deviation 3.55	-2.2 score on a scale Standard Deviation 3.29

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at a specific timepoint.

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, night time 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,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,2=mild,3=moderate,4=severe,5=very severe. Individual Item scores are added to yield a possible total score of 0 to 144. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=192 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=123 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=148 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the NPI Total Score	-12.3 score on a scale Standard Deviation 17.06	-9.5 score on a scale Standard Deviation 18.41	-16.9 score on a scale Standard Deviation 18.05

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at specific timepoint.

The CGIS-Agitation is an observer-rated scale that measures illness severity. The CGIS-Agitation is a 7-point (1-7) scale (1=normal, not at all ill participants; 7=among the most extremely ill participants) and is assessed for severity of agitation. A value of 0 is given to participants who are not assessed. Higher scores indicate poor health of participants. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=190 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=118 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=141 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score	-0.7 score on a scale Standard Deviation 0.85	-0.7 score on a scale Standard Deviation 0.92	-0.8 score on a scale Standard Deviation 0.93

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at a specific timepoint.

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. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=188 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=118 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=141 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Overall Rating	3.2 score on a scale Standard Deviation 1.20	3.4 score on a scale Standard Deviation 1.31	3.1 score on a scale Standard Deviation 1.23

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at a specific timepoint.

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. Higher scores indicate less response to treatment. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=191 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=118 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=141 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Patient Global Impression of Change (PGIC) Score	3.1 score on a scale Standard Deviation 1.01	3.1 score on a scale Standard Deviation 1.07	2.9 score on a scale Standard Deviation 1.05

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at specific timepoint.

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. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=153 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=96 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=117 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Dementia Quality of Life (DEMQOL) Score	2.9 score on a scale Standard Deviation 11.10	3.8 score on a scale Standard Deviation 8.10	3.2 score on a scale Standard Deviation 8.74

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at specific timepoint.

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 depression). 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. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=189 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=118 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=141 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline in the Cornell Scale for Depression in Dementia (CSDD) Score	-1.1 score on a scale Standard Deviation 2.84	-0.5 score on a scale Standard Deviation 2.90	-1.5 score on a scale Standard Deviation 2.57

SECONDARY outcome

Timeframe: Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number of participants analysed signifies the number of participants with available data for analysis at a specific timepoint.

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. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=210 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=150 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=158 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Poor to Missing	1 Participants	4 Participants	0 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Fair to Excellent to Very Good	6 Participants	6 Participants	3 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Poor to Excellent to Very Good	22 Participants	7 Participants	10 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Good to Good	17 Participants	9 Participants	10 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Fair to Good	80 Participants	65 Participants	65 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Poor to Good	6 Participants	6 Participants	4 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Missing to Good	1 Participants	0 Participants	0 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Good to Fair	53 Participants	31 Participants	43 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Fair to Fair	11 Participants	6 Participants	11 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Poor to Fair	0 Participants	3 Participants	1 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Fair to Poor	1 Participants	0 Participants	0 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Good to Missing	5 Participants	4 Participants	7 Participants
Number of Participants With the Change From Baseline in the General Medical Health Rating (GMHR) Score at Week 12 Fair to Missing	7 Participants	9 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: mITT Population included all randomized participants who had at least one post-baseline efficacy assessment. Participants were included in the treatment group to which they were randomized regardless of treatment received. Overall number analysed signifies the number of participants with available data for analysis at specific timepoint.

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. Negative change from baseline indicates less cognitive impairment. MMRM method was used for analysis.

Outcome measures

Outcome measures
Measure	Placebo n=143 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=91 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=97 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Change From Baseline to Week 12 in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score	-2.0 score on a scale Standard Deviation 5.67	-1.0 score on a scale Standard Deviation 7.36	-1.5 score on a scale Standard Deviation 6.38

SECONDARY outcome

Timeframe: Week 12

The RUD evaluates dementia participants' utilization of formal and informal healthcare resources, including hospitalizations and doctor visits, living assistance, and time spent by nonprofessional caregivers. Information on hours per day the caregiver spent assisting participant were reported in this outcome measure, using the following questions: Q1= On a typical care day during the last 30 days, how much time per day did you assist the participant with tasks such as toilet visits, eating, dressing, grooming, walking and bathing? Q2= On a typical care day during the last 30 days, how much time per day did you assist the participant with tasks such as shopping, food preparation, housekeeping, laundry, transportation, taking medication and managing financial matters? Q3= On a typical care day during the last 30 days, how much time per day did you spend supervising (that is, preventing dangerous events) the participant?

Outcome measures

Outcome measures
Measure	Placebo n=210 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=150 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=159 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Resource Utilization in Dementia (RUD) Score: Number of Hours Per Day the Caregiver Spent Assisting the Participant Q1	3.0 hours Interval 0.0 to 24.0	3.0 hours Interval 0.0 to 18.0	3.0 hours Interval 0.0 to 24.0
Resource Utilization in Dementia (RUD) Score: Number of Hours Per Day the Caregiver Spent Assisting the Participant Q2	4.5 hours Interval 0.0 to 24.0	5.0 hours Interval 0.0 to 24.0	5.0 hours Interval 0.0 to 24.0
Resource Utilization in Dementia (RUD) Score: Number of Hours Per Day the Caregiver Spent Assisting the Participant Q3	5.0 hours Interval 0.0 to 24.0	4.0 hours Interval 0.0 to 24.0	6.0 hours Interval 0.0 to 24.0

SECONDARY outcome

Timeframe: Week 12

The RUD evaluates dementia participants' utilization of formal and informal healthcare resources, including hospitalizations, doctor visits, living assistance, and time spent by nonprofessional caregivers. Information on days the caregiver spent assisting participant were reported in this outcome measure, using the following questions: Q1= During the last 30 days, how many days did you spend providing these (toilet visits, eating, dressing, grooming, walking and bathing) services to the participant? Q2= During the last 30 days, how many days did you spend providing these (shopping, food preparation, housekeeping, laundry, transportation, taking medication and managing financial matters) services to the participant? Q3= During the last 30 days, how many days did you spend providing these services (supervising) to the participant?

Outcome measures

Outcome measures
Measure	Placebo n=210 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=150 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=159 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Q1	30.0 days Interval 0.0 to 30.0	30.0 days Interval 0.0 to 30.0	30.0 days Interval 0.0 to 30.0
Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Q2	30.0 days Interval 0.0 to 30.0	30.0 days Interval 0.0 to 30.0	30.0 days Interval 0.0 to 30.0
Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Q3	30.0 days Interval 0.0 to 30.0	30.0 days Interval 0.0 to 30.0	30.0 days Interval 0.0 to 30.0

SECONDARY outcome

Timeframe: Week 12

The RUD evaluates dementia participants' utilization of formal and informal healthcare resources, including hospitalizations, doctor visits, living assistance, and time spent by nonprofessional caregivers. Information on the number of hospital visits, emergency visits and visits to healthcare professional were reported in this outcome measure using the following questions: Q1= During the last 30 days, how many times did the participant receive care in a hospital emergency room (for less than 24 hours)? Q2= During the last 30 days, how many times did the caregiver receive care in a hospital emergency room (for less than 24 hours)? Q3= During the last 30 days total number of visits by participant to a health care professional? Q4= During the last 30 days, how many times (number of visits for each) the participant visited any other health care professional?

Outcome measures

Outcome measures
Measure	Placebo n=210 Participants Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=150 Participants Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=159 Participants Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Resource Utilization in Dementia (RUD) Score: Number of Visits to Hospital, Emergency, and Healthcare Professional Q1	1.0 Number of visits Standard Deviation 0.0	1.3 Number of visits Standard Deviation 0.58	1.3 Number of visits Standard Deviation 0.58
Resource Utilization in Dementia (RUD) Score: Number of Visits to Hospital, Emergency, and Healthcare Professional Q2	1.0 Number of visits Standard Deviation NA SD cannot be calculated for 1 participant.	—	1.0 Number of visits Standard Deviation 0.00
Resource Utilization in Dementia (RUD) Score: Number of Visits to Hospital, Emergency, and Healthcare Professional Q3	2.7 Number of visits Standard Deviation 1.35	2.5 Number of visits Standard Deviation 1.28	2.6 Number of visits Standard Deviation 1.45
Resource Utilization in Dementia (RUD) Score: Number of Visits to Hospital, Emergency, and Healthcare Professional Q4	2.2 Number of visits Standard Deviation 0.88	2.1 Number of visits Standard Deviation 0.51	2.0 Number of visits Standard Deviation 0.59

Adverse Events

Placebo

Serious events: 10 serious events

Other events: 40 other events

Deaths: 0 deaths

AVP-786-28

Serious events: 15 serious events

Other events: 31 other events

Deaths: 3 deaths

AVP-786-42.63

Serious events: 8 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=210 participants at risk Participants were administered AVP-786 matching placebo capsules, orally, BID for up to 12 weeks.	AVP-786-28 n=151 participants at risk Participants were administered AVP-786-18 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-18 capsules, orally, BID during Weeks 2, 3 and AVP-786-28 capsules, orally, BID during Weeks 4 to 12.	AVP-786-42.63 n=160 participants at risk Participants were administered AVP-786-28 capsule, orally, QD along with AVP-786 matching placebo capsule, orally, QD during Week 1 followed by AVP-786-28 capsules, orally, BID during Weeks 2, 3 and AVP-786-42.63 capsules, orally, BID during Weeks 4 to 12.
Gastrointestinal disorders Diarrhoea	6.7% 14/210 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	3.3% 5/151 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	3.1% 5/160 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.
Infections and infestations Urinary tract infection	5.2% 11/210 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	6.6% 10/151 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	1.9% 3/160 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.
Injury, poisoning and procedural complications Fall	3.8% 8/210 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	9.9% 15/151 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	6.2% 10/160 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.
Nervous system disorders Somnolence	0.95% 2/210 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	2.6% 4/151 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	6.9% 11/160 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.
Psychiatric disorders Agitation	5.7% 12/210 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	1.3% 2/151 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.	2.5% 4/160 • From first dose up to 30 days after the last dose of study drug (up to 16 weeks) All-cause mortality: All Randomized Population included all the participants who were randomized in the study. Adverse events: Safety Population included all participants who received at least one dose of study medication. Participants were included in the treatment group based on the actual treatment received.

Additional Information

Global Clinical Development

Otsuka Pharmaceutical Development & Commercialization, Inc.

Phone: 1-609-524-6788

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place