Trial Outcomes & Findings for Efficacy, Safety and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type (NCT NCT02442765)

Last Updated: 2023-02-13

Results Overview

The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. The CMAI consists of 29 agitated behaviors that are 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. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

387 participants

Primary outcome timeframe

Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Results posted on

2023-02-13

Participant Flow

Total of 695 participants were screened of these, 308 participants failed screening, 387 participants were randomized out of which 382 participants had at least 1 post baseline efficacy assessment. (Modified Intent-to-Treat { mITT} population).

This study was conducted in 2 stages. 387 participants were randomized to treatment in Stage 1 and all the participants completed Stage 1 and were re-randomized into Stage 2 to compare AVP-786 28 mg, AVP-786 18 mg and placebo in parallel group (PG) design. In Stage 2, participants randomized to active treatment in Stage 1 (AVP-786-18 or AVP-786-28) continued to receive the same treatment and those randomized to placebo in Stage 1 were re-randomized to AVP-786-18, AVP-786-28, or placebo.

Participant milestones

Participant milestones
Measure	Stage 1: Placebo Participants received matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to Participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 2: Placebo Participants who received matching placebo orally BID for 6 consecutive weeks in Stage 1 were re-randomized in Stage 2 to receive the study drug or placebo from Day 43 to Day 85.	Stage 1: Placebo to: Stage 2: AVP-786-28 d6-DM 18 mg/Q 4.9 mg Participants who were placebo responders or non-responders in Stage 1 received AVP-786-18 for 1 week, orally, QD, followed by AVP-786-18 BID for 2 weeks; followed by AVP-786-28 BID for the last 3 weeks..	Stage 1: Placebo to: Stage 2: AVP-786-28 d6 DM 28 mg/Q 4.9 mg Participants who were placebo responders or non-responders in Stage 1 received AVP-786-28 for 1 week, orally, QD, followed by AVP-786-28 BID for 2 weeks; followed by AVP-786-28 BID for the last 3 weeks.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) to: Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) Participants who received AVP-786-18 mg in Stage 1 continued to receive AVP-786-18 mg orally BID for the 6 weeks (Days 43-85) in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received AVP-786-28 mg in Stage 1 continued to receive AVP-786-28 mg orally BID for 6 weeks (Days 43-85) in Stage 2.
Stage 1- (Days 1 to 42) STARTED	194	96	97	0	0	0	0	0
Stage 1- (Days 1 to 42) COMPLETED	194	96	97	0	0	0	0	0
Stage 1- (Days 1 to 42) NOT COMPLETED	0	0	0	0	0	0	0	0
Stage 2- (Days 43 to 85) STARTED	0	0	0	63	96	97	65	66
Stage 2- (Days 43 to 85) COMPLETED	0	0	0	56	86	92	59	55
Stage 2- (Days 43 to 85) NOT COMPLETED	0	0	0	7	10	5	6	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Stage 2: Placebo Participants who received matching placebo orally BID for 6 consecutive weeks in Stage 1 were re-randomized in Stage 2 to receive the study drug or placebo from Day 43 to Day 85.	Stage 1: Placebo to: Stage 2: AVP-786-28 d6-DM 18 mg/Q 4.9 mg Participants who were placebo responders or non-responders in Stage 1 received AVP-786-18 for 1 week, orally, QD, followed by AVP-786-18 BID for 2 weeks; followed by AVP-786-28 BID for the last 3 weeks..	Stage 1: Placebo to: Stage 2: AVP-786-28 d6 DM 28 mg/Q 4.9 mg Participants who were placebo responders or non-responders in Stage 1 received AVP-786-28 for 1 week, orally, QD, followed by AVP-786-28 BID for 2 weeks; followed by AVP-786-28 BID for the last 3 weeks.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) to: Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) Participants who received AVP-786-18 mg in Stage 1 continued to receive AVP-786-18 mg orally BID for the 6 weeks (Days 43-85) in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received AVP-786-28 mg in Stage 1 continued to receive AVP-786-28 mg orally BID for 6 weeks (Days 43-85) in Stage 2.
Stage 2- (Days 43 to 85) Reason not specified	0	1	0	0	1
Stage 2- (Days 43 to 85) Adverse Event	2	6	1	1	5
Stage 2- (Days 43 to 85) Death	1	1	0	2	0
Stage 2- (Days 43 to 85) Lack of Efficacy	1	0	0	0	0
Stage 2- (Days 43 to 85) Protocol Deviation	1	0	0	0	0
Stage 2- (Days 43 to 85) Study Participant Withdrawal by Parent or Guardian	1	0	1	0	4
Stage 2- (Days 43 to 85) Lost to Follow-up	1	0	3	1	0
Stage 2- (Days 43 to 85) Withdrawal by Subject	0	2	0	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=191 Participants In Stage 1, participants received matching placebo orally twice daily (BID).	AVP-786-18 n=94 Participants In Stage 1, participants received AVP-786-18 orally once daily (OD) in the morning and placebo orally OD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks. In Stage 2, participants continued to receive AVP-786-18 mg orally BID for 6 consecutive weeks.	AVP-786-28 n=97 Participants In Stage 1, participants received AVP-786-18 mg orally OD in the morning and placebo orally OD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks. From Day 22, participants received AVP-786-28 orally BID for the remaining 3 weeks. In Stage 2, participants continued to receive AVP-786-28 mg orally BID for 6 consecutive weeks.	Total n=382 Participants Total of all reporting groups
Age, Continuous	76.6 years STANDARD_DEVIATION 7.92 • n=5 Participants	73.8 years STANDARD_DEVIATION 8.39 • n=7 Participants	74.6 years STANDARD_DEVIATION 7.69 • n=5 Participants	75.4 years STANDARD_DEVIATION 8.06 • n=4 Participants
Sex: Female, Male Female	112 Participants n=5 Participants	47 Participants n=7 Participants	54 Participants n=5 Participants	213 Participants n=4 Participants
Sex: Female, Male Male	79 Participants n=5 Participants	47 Participants n=7 Participants	43 Participants n=5 Participants	169 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	12 Participants n=5 Participants	6 Participants n=7 Participants	6 Participants n=5 Participants	24 Participants n=4 Participants
Race (NIH/OMB) White	175 Participants n=5 Participants	87 Participants n=7 Participants	89 Participants n=5 Participants	351 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 Modified Intent-to-Treat (mITT) Population: all participants randomized in Stage 1 who had at least 1 post-Baseline efficacy assessment. Stage 2 mITT Population: all participants randomized in Stage 2 who had at least 1 efficacy assessment in Stage 2. Data were reported for only those participants contributing data to the analysis.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=188 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=92 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=40 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-1.6 units on a scale Standard Deviation 11.08	-5.6 units on a scale Standard Deviation 11.78	-4.9 units on a scale Standard Deviation 12.13
Stage 1 and Stage 2: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score to Week 6 and Week 12 Stage 1 Baseline	73.9 units on a scale Standard Deviation 22.23	72.3 units on a scale Standard Deviation 23.08	71.7 units on a scale Standard Deviation 23.57	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score to Week 6 and Week 12 Change from Baseline at Week 6	-10.7 units on a scale Standard Deviation 15.29	-13.9 units on a scale Standard Deviation 16.70	-10.3 units on a scale Standard Deviation 13.54	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	66.0 units on a scale Standard Deviation 24.71	68.9 units on a scale Standard Deviation 20.79	65.3 units on a scale Standard Deviation 19.36

SECONDARY outcome

Timeframe: Stage 1 Week 6; Stage 2 Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=184 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=90 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=96 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=40 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=42 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Least Squares Mean Modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC)-Agitation Score at Week 6 and Week 12 Stage 1 Week 6	3.4 score on a scale Standard Error 1.13	3.2 score on a scale Standard Error 1.24	3.3 score on a scale Standard Error 1.12	—	—	—
Least Squares Mean Modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC)-Agitation Score at Week 6 and Week 12 Stage 2 Week 12	—	—	—	3.9 score on a scale Standard Error 0.18	3.3 score on a scale Standard Error 0.18	3.5 score on a scale Standard Error 0.17

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score to Week 6 and Week 12 Stage 1 Baseline	7.1 units on a scale Standard Deviation 2.39	6.5 units on a scale Standard Deviation 1.94	7.2 units on a scale Standard Deviation 2.42	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score to Week 6 and Week 12 Change from Baseline at Week 6	-1.8 units on a scale Standard Deviation 3.58	-2.0 units on a scale Standard Deviation 3.03	-2.1 units on a scale Standard Deviation 2.94	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	6.9 units on a scale Standard Deviation 2.84	6.3 units on a scale Standard Deviation 2.71	6.3 units on a scale Standard Deviation 2.81
Stage 1 and Stage 2: Change From Baseline in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-1.7 units on a scale Standard Deviation 3.00	-0.8 units on a scale Standard Deviation 3.15	-0.9 units on a scale Standard Deviation 3.35

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=164 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=77 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=85 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=39 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=38 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=43 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the NPI Caregiver Distress Score to Week 6 and Week 12 Stage 1 Baseline	18.87 units on a scale Standard Deviation 9.026	18.90 units on a scale Standard Deviation 9.266	18.88 units on a scale Standard Deviation 10.015	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Caregiver Distress Score to Week 6 and Week 12 Change from Baseline at Week 6	-4.31 units on a scale Standard Deviation 7.979	-5.48 units on a scale Standard Deviation 8.559	-4.83 units on a scale Standard Deviation 7.736	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Caregiver Distress Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	17.33 units on a scale Standard Deviation 9.010	15.95 units on a scale Standard Deviation 7.241	16.89 units on a scale Standard Deviation 7.416
Stage 1 and Stage 2: Change From Baseline in the NPI Caregiver Distress Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-0.73 units on a scale Standard Deviation 6.533	-1.67 units on a scale Standard Deviation 5.666	0.44 units on a scale Standard Deviation 7.265

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the NPI Aberrant Motor Behavior Domain Score to Week 6 and Week 12 Stage 1 Baseline	5.1 units on a scale Standard Deviation 3.94	4.9 units on a scale Standard Deviation 3.77	5.1 units on a scale Standard Deviation 4.07	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Aberrant Motor Behavior Domain Score to Week 6 and Week 12 Change from Baseline at Week 6 Stage 2 Baseline	-0.9 units on a scale Standard Deviation 3.62	-1.6 units on a scale Standard Deviation 3.74	-0.7 units on a scale Standard Deviation 3.86	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Aberrant Motor Behavior Domain Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	5.2 units on a scale Standard Deviation 3.79	4.0 units on a scale Standard Deviation 3.87	4.3 units on a scale Standard Deviation 4.32
Stage 1 and Stage 2: Change From Baseline in the NPI Aberrant Motor Behavior Domain Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-0.4 units on a scale Standard Deviation 2.16	0.6 units on a scale Standard Deviation 3.24	1.1 units on a scale Standard Deviation 3.54

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Overall number of participants analyzed are the number of participants with data available for analysis at given time point.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the Zarit Burden Interview (ZBI) Score to Week 6 and Week 12 Stage 1 Baseline	30.9 units on a scale Standard Deviation 16.19	30.0 units on a scale Standard Deviation 16.96	33.0 units on a scale Standard Deviation 16.68	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Zarit Burden Interview (ZBI) Score to Week 6 and Week 12 Change from Baseline at Week 6	-1.4 units on a scale Standard Deviation 8.22	-2.0 units on a scale Standard Deviation 8.44	-2.7 units on a scale Standard Deviation 9.49	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Zarit Burden Interview (ZBI) Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	31.5 units on a scale Standard Deviation 15.24	32.0 units on a scale Standard Deviation 16.57	28.6 units on a scale Standard Deviation 16.76
Stage 1 and Stage 2: Change From Baseline in the Zarit Burden Interview (ZBI) Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-1.1 units on a scale Standard Deviation 7.65	1.4 units on a scale Standard Deviation 8.71	-0.5 units on a scale Standard Deviation 7.05

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2: mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the NPI Irritability/Lability Domain Score to Week 6 and Week 12 Stage 1 Baseline	5.1 units on a scale Standard Deviation 3.33	5.1 units on a scale Standard Deviation 3.62	5.2 units on a scale Standard Deviation 3.39	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Irritability/Lability Domain Score to Week 6 and Week 12 Change from Baseline at Week 6	-1.1 units on a scale Standard Deviation 3.84	-1.9 units on a scale Standard Deviation 3.71	-1.4 units on a scale Standard Deviation 3.62	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Irritability/Lability Domain Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	4.5 units on a scale Standard Deviation 3.99	5.3 units on a scale Standard Deviation 3.54	5.2 units on a scale Standard Deviation 3.64
Stage 1 and Stage 2: Change From Baseline in the NPI Irritability/Lability Domain Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	0.2 units on a scale Standard Deviation 3.19	-1.3 units on a scale Standard Deviation 3.88	-0.9 units on a scale Standard Deviation 3.45

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the NPI Total Score to Week 6 and Week 12 Stage 1 Baseline	40.2 units on a scale Standard Deviation 17.95	39.4 units on a scale Standard Deviation 18.93	40.1 units on a scale Standard Deviation 19.98	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Total Score to Week 6 and Week 12 Change from Baseline at Week 6	-9.2 units on a scale Standard Deviation 17.41	-13.2 units on a scale Standard Deviation 17.99	-10.6 units on a scale Standard Deviation 16.09	—	—	—
Stage 1 and Stage 2: Change From Baseline in the NPI Total Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	39.2 units on a scale Standard Deviation 22.47	34.7 units on a scale Standard Deviation 14.16	34.6 units on a scale Standard Deviation 16.93
Stage 1 and Stage 2: Change From Baseline in the NPI Total Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-5.1 units on a scale Standard Deviation 14.03	-4.4 units on a scale Standard Deviation 12.92	-0.1 units on a scale Standard Deviation 18.82

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score to Week 6 and Week 12 Stage 1 Baseline	4.5 units on a scale Standard Deviation 0.64	4.3 units on a scale Standard Deviation 0.49	4.4 units on a scale Standard Deviation 0.70	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score to Week 6 and Week 12 Change from Baseline at Week 6	-0.5 units on a scale Standard Deviation 0.78	-0.7 units on a scale Standard Deviation 0.97	-0.7 units on a scale Standard Deviation 1.04	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	4.4 units on a scale Standard Deviation 0.87	4.2 units on a scale Standard Deviation 0.77	4.1 units on a scale Standard Deviation 0.77
Stage 1 and Stage 2: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-0.2 units on a scale Standard Deviation 0.58	-0.4 units on a scale Standard Deviation 0.70	-0.3 units on a scale Standard Deviation 1.01

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=183 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=90 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=96 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=40 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=42 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Rating at Week 6 and Week 12 Stage 1 Week 6	3.7 units on a scale Standard Error 0.11	3.5 units on a scale Standard Error 0.14	3.6 units on a scale Standard Error 0.13	—	—	—
Stage 1 and Stage 2: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Rating at Week 6 and Week 12 Stage 2 Week 12	—	—	—	4.0 units on a scale Standard Error 0.17	3.6 units on a scale Standard Error 0.17	3.7 units on a scale Standard Error 0.16

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=185 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=90 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=96 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Patient Global Impression of Change (PGIC) Score at Week 6 and Week 12 Stage 1 Week 6	3.4 units on a scale Standard Error 0.12	3.0 units on a scale Standard Error 0.15	3.1 units on a scale Standard Error 0.14	—	—	—
Stage 1 and Stage 2: Patient Global Impression of Change (PGIC) Score at Week 6 and Week 12 Stage 2 Week 12	—	—	—	3.6 units on a scale Standard Error 0.20	3.1 units on a scale Standard Error 0.20	3.3 units on a scale Standard Error 0.19

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=133 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=69 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=72 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=24 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=30 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=32 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score to Week 6 and Week 12 Stage 1 Baseline	85.7 units on a scale Standard Deviation 10.63	82.9 units on a scale Standard Deviation 10.22	84.0 units on a scale Standard Deviation 11.98	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score to Week 6 and Week 12 Change from Baseline at Week 6	2.3 units on a scale Standard Deviation 8.26	3.5 units on a scale Standard Deviation 8.57	4.4 units on a scale Standard Deviation 10.79	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	86.8 units on a scale Standard Deviation 9.96	90.0 units on a scale Standard Deviation 9.51	87.8 units on a scale Standard Deviation 10.72
Stage 1 and Stage 2: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	2.5 units on a scale Standard Deviation 5.40	3.1 units on a scale Standard Deviation 9.52	1.1 units on a scale Standard Deviation 13.06

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=40 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=41 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=44 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the Cornell Scale for Depression in Dementia (CSDD) Score to Week 6 and Week 12 Stage 1 Baseline	6.2 units on a scale Standard Deviation 2.24	6.3 units on a scale Standard Deviation 2.11	6.4 units on a scale Standard Deviation 2.19	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Cornell Scale for Depression in Dementia (CSDD) Score to Week 6 and Week 12 Change from Baseline at Week 6	-0.3 units on a scale Standard Deviation 3.01	-0.7 units on a scale Standard Deviation 3.09	-0.5 units on a scale Standard Deviation 2.93	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Cornell Scale for Depression in Dementia (CSDD) Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	6.6 units on a scale Standard Deviation 3.89	5.9 units on a scale Standard Deviation 2.78	6.8 units on a scale Standard Deviation 2.84
Stage 1 and Stage 2: Change From Baseline in the Cornell Scale for Depression in Dementia (CSDD) Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-0.4 units on a scale Standard Deviation 2.56	-0.5 units on a scale Standard Deviation 2.36	-0.3 units on a scale Standard Deviation 3.09

SECONDARY outcome

Timeframe: Baseline; Week 12

Population: Stage 2 mITT population included all participants who were rerandomized in Stage 2 and had at least 1 efficacy assessment in Stage 2 (after Week 6). The data is reported for stage 2 only. Overall number analyzed are the number of participants with data available for analyses. The percentages are rounded off to the nearest whole number.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=62 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=64 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=65 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=94 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=97 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 2: Percentage of Participants With General Medical Health Rating (GMHR) Score Excellent to very good	22.6 percentage of participants	20.3 percentage of participants	13.8 percentage of participants	20.2 percentage of participants	20.6 percentage of participants	—
Stage 2: Percentage of Participants With General Medical Health Rating (GMHR) Score Good	59.7 percentage of participants	64.1 percentage of participants	58.5 percentage of participants	58.5 percentage of participants	62.9 percentage of participants	—
Stage 2: Percentage of Participants With General Medical Health Rating (GMHR) Score Fair	11.3 percentage of participants	7.8 percentage of participants	16.9 percentage of participants	13.8 percentage of participants	11.3 percentage of participants	—
Stage 2: Percentage of Participants With General Medical Health Rating (GMHR) Score Poor	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants	—
Stage 2: Percentage of Participants With General Medical Health Rating (GMHR) Score Missing	6.5 percentage of participants	7.8 percentage of participants	10.8 percentage of participants	7.4 percentage of participants	5.2 percentage of participants	—

SECONDARY outcome

Timeframe: Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Population: Stage 1 and Stage 2 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=131 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=68 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=71 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=25 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=29 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=32 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1 and Stage 2: Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score to Week 6 and Week 12 Stage 1 Baseline	25.8 units on a scale Standard Deviation 10.10	26.2 units on a scale Standard Deviation 8.99	25.3 units on a scale Standard Deviation 8.88	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score to Week 6 and Week 12 Change from Baseline at Week 6	-0.5 units on a scale Standard Deviation 4.46	-2.0 units on a scale Standard Deviation 4.28	-0.5 units on a scale Standard Deviation 4.72	—	—	—
Stage 1 and Stage 2: Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score to Week 6 and Week 12 Stage 2 Baseline	—	—	—	26.9 units on a scale Standard Deviation 9.56	27.0 units on a scale Standard Deviation 9.27	25.3 units on a scale Standard Deviation 10.91
Stage 1 and Stage 2: Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score to Week 6 and Week 12 Change from Baseline at Week 12	—	—	—	-0.8 units on a scale Standard Deviation 5.05	0.3 units on a scale Standard Deviation 4.95	0.1 units on a scale Standard Deviation 5.47

SECONDARY outcome

Timeframe: Stage 1: Week 6

Population: Stage 1 mITT Populations. Data were reported for only those participants contributing data to the analysis. Number analyzed are the number of participants available at the given timepoint.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1: Resource Utilization in Dementia (RUD): Percentage of Caregiver Who Reported That Their Responsibilities Affected Their Work and Who Visited Health Care Professionals Caregivers Who Reported that their Responsibilities Affected Their Work	33.8 percentage of participants	22.9 percentage of participants	34.2 percentage of participants	—	—	—
Stage 1: Resource Utilization in Dementia (RUD): Percentage of Caregiver Who Reported That Their Responsibilities Affected Their Work and Who Visited Health Care Professionals Caregivers Who Visited Health Care Professionals	42.2 percentage of participants	31.1 percentage of participants	44.8 percentage of participants	—	—	—

SECONDARY outcome

Timeframe: Stage 2: Week 12

Population: Stage 2 mITT Population. Data were reported for only those participants contributing data to the analysis. Number analyzed are the number of participants available at the given timepoint.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=62 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=59 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=60 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=94 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=97 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 2: Resource Utilization in Dementia (RUD): Percentage of Caregiver Who Reported That Their Responsibilities Affected Their Work and Who Visited Health Care Professionals Caregivers Who Reported that their Responsibilities Affected Their Work	44.0 percentage of participants	28.6 percentage of participants	36.4 percentage of participants	24.2 percentage of participants	35.3 percentage of participants	—
Stage 2: Resource Utilization in Dementia (RUD): Percentage of Caregiver Who Reported That Their Responsibilities Affected Their Work and Who Visited Health Care Professionals Caregivers Who Visited Health Care Professionals	43.1 percentage of participants	30.5 percentage of participants	29.3 percentage of participants	26.7 percentage of participants	37.0 percentage of participants	—

SECONDARY outcome

Timeframe: Stage 1: Week 6

Population: Stage 1 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=171 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=84 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=90 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant Week 6 (Q1)	2.0 hours Interval 0.0 to 20.0	2.0 hours Interval 0.0 to 24.0	2.0 hours Interval 0.0 to 15.0	—	—	—
Stage 1: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant Week 6 (Q2)	4.0 hours Interval 1.0 to 24.0	4.0 hours Interval 0.0 to 18.0	4.0 hours Interval 1.0 to 15.0	—	—	—
Stage 1: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant Week 6 (Q3)	3.0 hours Interval 0.0 to 24.0	2.0 hours Interval 0.0 to 24.0	2.8 hours Interval 0.0 to 24.0	—	—	—

SECONDARY outcome

Timeframe: Stage 2: Week 12

Population: Stage 2 mITT Population. The data is reported for stage 2 only. Data were reported for only those participants contributing data to the analysis

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=54 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=55 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=53 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo n=81 Participants Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=87 Participants Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 2: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant Week 12 (Q1)	1.5 hours Interval 0.0 to 15.0	2.0 hours Interval 0.0 to 7.0	2.0 hours Interval 0.0 to 12.0	2.0 hours Interval 0.0 to 10.0	2.0 hours Interval 0.0 to 14.0	—
Stage 2: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant Week 12 (Q2)	4.0 hours Interval 0.0 to 16.0	4.0 hours Interval 0.0 to 24.0	4.0 hours Interval 0.0 to 24.0	4.0 hours Interval 0.0 to 17.0	4.0 hours Interval 0.0 to 15.0	—
Stage 2: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant Week 12 (Q3)	1.0 hours Interval 0.0 to 19.0	3.0 hours Interval 0.0 to 24.0	3.0 hours Interval 0.0 to 20.0	2.0 hours Interval 0.0 to 24.0	2.0 hours Interval 0.0 to 18.0	—

SECONDARY outcome

Timeframe: Stage 1: Week 6

Population: Stage 1 mITT Populations. Data were reported for only those participants contributing data to the analysis.

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=191 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
Stage 1: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Week 6 (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	—	—	—
Stage 1: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Week 6 (Q2)	30.0 days Interval 0.0 to 30.0	30.0 days Interval 0.0 to 39.0	30.0 days Interval 4.0 to 30.0	—	—	—
Stage 1: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Week 6 (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: 12-Week Parallel Group: Week 12

Population: mITT 12-Week Parallel-Group Population included all participants in the 12-Week Parallel Group who have at least one post-baseline efficacy assessment

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.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=62 Participants Participants received a matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) n=94 Participants Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) n=97 Participants Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 22-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: Placebo Participants who received matching placebo in Stage 1 and were classified as non-responders (participants randomized to placebo in Stage 1 whose Clinical Global Impression of Severity of Illness scale for Agitation (CGIS-Agitation) score was ≤ 3 at Visit 4 (Day 43) and NPI- Agitation/Aggression Domain score has decreased by ≥ 25% from Baseline) were re-randomized to placebo and continued to receive placebo BID from Day 43 to Day 85 in Stage 2.	Stage 1: Placebo Non-responders to Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 50-85).	Stage 1: Placebo Non-responders to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) Participants who received matching placebo in Stage 1 and were classified non-responders were re-randomized in Stage 2 to receive AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days of Stage 2 (Days 43-49), followed by AVP-786-18 mg orally BID for 2 weeks (Days 50-63). From Day 64, participants received AVP-786-28 mg orally BID for the remaining 3 weeks (Days 64-85).
12-Week Parallel Group: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Week 12 (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	—	—	—
12-Week Parallel Group: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Week 12 (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	—	—	—
12-Week Parallel Group: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant Week 12 (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	—	—	—

Adverse Events

Placebo

Serious events: 6 serious events

Other events: 84 other events

Deaths: 1 deaths

AVP-786-18

Serious events: 17 serious events

Other events: 78 other events

Deaths: 3 deaths

AVP-786-28

Serious events: 7 serious events

Other events: 71 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

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