Trial Outcomes & Findings for Efficacy, Safety and Tolerability Study of AVP-923 (Dextromethorphan/Quinidine) for Treatment of Symptoms of Agitation in Participants With Alzheimer's Disease (NCT NCT01584440)

Results Overview

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 was 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, marked. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. Data are reported for only those participants contributing data to the analysis.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

220 participants

Primary outcome timeframe

Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Results posted on

2021-11-26

Participant Flow

Participant milestones

Participant milestones
Measure	Stage 1: AVP-923 Participants received oral AVP-923 during Stage 1 for 5 consecutive weeks. Participants received AVP-923-20 once daily (QD) in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 1 (Days 1 to 7), AVP-923-20 twice a day (BID) during the next 2 consecutive weeks (Days 8 to 21), and AVP-923-30 BID during the final 2 weeks of Stage 1 (Days 22 to 35). (AVP-923-20: 20 milligrams (mg) of dextromethorphan and 10 mg of quinidine; AVP-923-30: 30 mg of dextromethorphan and 10 mg of quinidine)	Stage 1: Placebo Participants received matching oral placebo during Stage 1 for 5 consecutive weeks.	AVP-923 in Stage 1/AVP-923 in Stage 2 Participants received oral AVP-923 during Stage 1 for 5 consecutive weeks. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 1 (Days 1 to 7), AVP-923-20 BID during the next 2 consecutive weeks (Days 8 to 21), and AVP-923-30 BID during the final 2 weeks of Stage 1 (Days 22 to 35). Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants continued to receive AVP-923-30 BID for the entire 5-week duration of Stage 2. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 2 (Days 36 to 42), AVP-923-20 BID during the next 2 consecutive weeks (Days 43 to 56), and AVP-923-30 BID during the final 2 weeks of Stage 2 (Days 57 to 70).	Placebo in Stage 1/AVP-923 in Stage 2 Participants received matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive AVP-923 in Stage 2. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 2 (Days 36 to 42), AVP-923-20 BID during the next 2 consecutive weeks (Days 43 to 56), and AVP-923-30 BID during the final 2 weeks of Stage 2 (Days 57 to 70).	Placebo in Stage 1/Placebo in Stage 2 Participants received matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Stage 1 (5 Weeks) STARTED	93	127	0	0	0
Stage 1 (5 Weeks) COMPLETED	83	119	0	0	0
Stage 1 (5 Weeks) NOT COMPLETED	10	8	0	0	0
Stage 2 (5 Weeks) STARTED	0	0	83	59	60
Stage 2 (5 Weeks) COMPLETED	0	0	80	55	59
Stage 2 (5 Weeks) NOT COMPLETED	0	0	3	4	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Stage 1: AVP-923 Participants received oral AVP-923 during Stage 1 for 5 consecutive weeks. Participants received AVP-923-20 once daily (QD) in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 1 (Days 1 to 7), AVP-923-20 twice a day (BID) during the next 2 consecutive weeks (Days 8 to 21), and AVP-923-30 BID during the final 2 weeks of Stage 1 (Days 22 to 35). (AVP-923-20: 20 milligrams (mg) of dextromethorphan and 10 mg of quinidine; AVP-923-30: 30 mg of dextromethorphan and 10 mg of quinidine)	Stage 1: Placebo Participants received matching oral placebo during Stage 1 for 5 consecutive weeks.	AVP-923 in Stage 1/AVP-923 in Stage 2 Participants received oral AVP-923 during Stage 1 for 5 consecutive weeks. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 1 (Days 1 to 7), AVP-923-20 BID during the next 2 consecutive weeks (Days 8 to 21), and AVP-923-30 BID during the final 2 weeks of Stage 1 (Days 22 to 35). Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants continued to receive AVP-923-30 BID for the entire 5-week duration of Stage 2. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 2 (Days 36 to 42), AVP-923-20 BID during the next 2 consecutive weeks (Days 43 to 56), and AVP-923-30 BID during the final 2 weeks of Stage 2 (Days 57 to 70).	Placebo in Stage 1/AVP-923 in Stage 2 Participants received matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive AVP-923 in Stage 2. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 2 (Days 36 to 42), AVP-923-20 BID during the next 2 consecutive weeks (Days 43 to 56), and AVP-923-30 BID during the final 2 weeks of Stage 2 (Days 57 to 70).	Placebo in Stage 1/Placebo in Stage 2 Participants received matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Stage 1 (5 Weeks) Advised Not to Take Study Medication	1	0	0	0	0
Stage 1 (5 Weeks) Adverse Event	5	3	0	0	0
Stage 1 (5 Weeks) Lost to Follow-up	1	0	0	0	0
Stage 1 (5 Weeks) Protocol Violation	2	3	0	0	0
Stage 1 (5 Weeks) Withdrawal by Subject	1	0	0	0	0
Stage 1 (5 Weeks) Withdrawal by Parent/Guardian	0	2	0	0	0
Stage 2 (5 Weeks) Withdrawal by Subject	0	0	1	2	0
Stage 2 (5 Weeks) Adverse Event	0	0	1	2	1
Stage 2 (5 Weeks) Unable to Return to Site: Rehabilitation	0	0	1	0	0

Baseline Characteristics

Efficacy, Safety and Tolerability Study of AVP-923 (Dextromethorphan/Quinidine) for Treatment of Symptoms of Agitation in Participants With Alzheimer's Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AVP-923 n=93 Participants Participants received oral AVP-923 during Stage 1 for 5 consecutive weeks. Participants received AVP-923-20 once daily (QD) in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 1 (Days 1 to 7), AVP-923-20 twice a day (BID) during the next 2 consecutive weeks (Days 8 to 21), and AVP-923-30 BID during the final 2 weeks of Stage 1 (Days 22 to 35).	Placebo n=125 Participants Participants received matching oral placebo during Stage 1 for 5 consecutive weeks.	Total n=218 Participants Total of all reporting groups
Age, Continuous	77.8 years STANDARD_DEVIATION 8.01 • n=5 Participants	77.6 years STANDARD_DEVIATION 7.19 • n=7 Participants	77.7 years STANDARD_DEVIATION 7.53 • n=5 Participants
Sex: Female, Male Female	52 Participants n=5 Participants	74 Participants n=7 Participants	126 Participants n=5 Participants
Sex: Female, Male Male	41 Participants n=5 Participants	51 Participants n=7 Participants	92 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) White	84 Participants n=5 Participants	116 Participants n=7 Participants	200 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 modified Intent-to-Treat (mITT) Population: all participants randomized in Stage 1 who had at least one post-Baseline NPI agitation/aggression score in Stage 1. Stage 2 mITT Population: all placebo non-responders from Stage 1 who were re-randomized in Stage 2 and had at least one post-Week 4 NPI agitation/aggression score in Stage 2

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 was 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, marked. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. Data are reported for only those participants contributing data to the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-1.7 score on a scale Standard Deviation 3.10	-3.3 score on a scale Standard Deviation 2.98	—
Change in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-0.8 score on a scale Standard Deviation 3.59	-2.0 score on a scale Standard Deviation 3.19	—

SECONDARY outcome

Timeframe: up to Week 10

Population: Safety Population: all randomized participants who received at least one dose of study treatment

Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days)

Outcome measures

Outcome measures
Measure	Placebo n=152 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=127 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Number of Participants With the Indicated Type of Adverse Event Participants with ≥ 1 TEAE	93 Participants	55 Participants	—
Number of Participants With the Indicated Type of Adverse Event Participants with discontinuations due to a TEAE	8 Participants	4 Participants	—
Number of Participants With the Indicated Type of Adverse Event Participants who died	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Population. Data are 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. 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. The total score is calculated as a sum of all 12 domain scores and thus ranges from 12 to 144. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Total NPI Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-8.5 score on a scale Standard Deviation 14.35	-13.5 score on a scale Standard Deviation 17.48	—
Change in the Total NPI Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-2.5 score on a scale Standard Deviation 11.82	-6.0 score on a scale Standard Deviation 2.48	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Population. Data are 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. 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. Sleep/nighttime behavior disorders = S/NB disorders.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Hallucinations	-0.4 score on a scale Standard Deviation 1.60	-0.1 score on a scale Standard Deviation 2.03	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Depression/dysphoria	0.2 score on a scale Standard Deviation 2.36	0.2 score on a scale Standard Deviation 2.20	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Anxiety	-0.3 score on a scale Standard Deviation 2.89	-1.0 score on a scale Standard Deviation 2.76	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Euphoria/elation	-0.0 score on a scale Standard Deviation 1.25	-0.2 score on a scale Standard Deviation 0.95	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Apathy/indifference	0.4 score on a scale Standard Deviation 1.96	-0.5 score on a scale Standard Deviation 3.43	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Disinhibition	-0.8 score on a scale Standard Deviation 2.51	-0.8 score on a scale Standard Deviation 2.67	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Irritability/lability	-0.7 score on a scale Standard Deviation 3.71	-1.0 score on a scale Standard Deviation 3.40	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Aberrant motor behavior	0.4 score on a scale Standard Deviation 3.15	-0.8 score on a scale Standard Deviation 2.52	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, S/NB disorders	-0.1 score on a scale Standard Deviation 2.04	0.0 score on a scale Standard Deviation 2.46	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Appetite/eating changes	0.4 score on a scale Standard Deviation 2.28	0.1 score on a scale Standard Deviation 2.73	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Delusions	-0.6 score on a scale Standard Deviation 2.93	-0.8 score on a scale Standard Deviation 2.89	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Hallucinations	-0.1 score on a scale Standard Deviation 1.68	0.2 score on a scale Standard Deviation 1.76	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Depression/dysphoria	-1.0 score on a scale Standard Deviation 2.89	-0.9 score on a scale Standard Deviation 2.49	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Anxiety	-1.2 score on a scale Standard Deviation 3.69	-0.6 score on a scale Standard Deviation 3.21	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Euphoria/elation	-0.1 score on a scale Standard Deviation 1.27	-0.3 score on a scale Standard Deviation 1.85	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Apathy/indifference	-0.5 score on a scale Standard Deviation 3.69	-0.9 score on a scale Standard Deviation 4.11	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Disinhibition	-0.7 score on a scale Standard Deviation 3.04	-0.9 score on a scale Standard Deviation 3.46	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Irritability/lability	-1.2 score on a scale Standard Deviation 3.23	-2.2 score on a scale Standard Deviation 4.08	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Aberrant motor behavior	-0.4 score on a scale Standard Deviation 3.95	-1.2 score on a scale Standard Deviation 3.98	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, S/NB disorders	-0.1 score on a scale Standard Deviation 2.50	-1.0 score on a scale Standard Deviation 3.82	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Appetite/eating changes	-1.2 score on a scale Standard Deviation 3.25	-1.2 score on a scale Standard Deviation 3.68	—
Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Delusions	-0.7 score on a scale Standard Deviation 3.09	0.1 score on a scale Standard Deviation 3.17	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Populations. Data are 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. 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. The NPI4D score is the sum of the Agitation/Aggression, Irritability/Lability, Disinhibition, and Aberrant Motor Behavior domain scores, and thus ranges from 4 to 48. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Sum of the Agitation/Aggression, Irritability/Lability, Disinhibition, and Aberrant Motor Behavior NPI Domain (NPI4D) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-4.0 score on a scale Standard Deviation 8.24	-7.6 score on a scale Standard Deviation 9.08	—
Change in the Sum of the Agitation/Aggression, Irritability/Lability, Disinhibition, and Aberrant Motor Behavior NPI Domain (NPI4D) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-1.9 score on a scale Standard Deviation 7.65	-4.6 score on a scale Standard Deviation 7.31	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Populations. Data are 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. 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. The NPI4A score is the sum of the Agitation/Aggression, Irritability/Lability, Anxiety, and Aberrant Motor Behavior domain scores, and thus ranges from 4 to 48. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Sum of the Agitation/Aggression, Irritability/Lability, Anxiety, and Aberrant Motor Behavior NPI Domain (NPI4A) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-4.5 score on a scale Standard Deviation 8.53	-7.3 score on a scale Standard Deviation 9.08	—
Change in the Sum of the Agitation/Aggression, Irritability/Lability, Anxiety, and Aberrant Motor Behavior NPI Domain (NPI4A) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-1.4 score on a scale Standard Deviation 7.94	-4.8 score on a scale Standard Deviation 7.05	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Populations. Data are 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. For each domain, the caregiver is asked to rate how emotionally distressing they find the symptom behavior on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. The total NPI-CDS score is calculated as the sum of all 12 domain scores and thus ranges from 0 to 60. A higher score represents increased distress. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Total Neuropsychiatric Inventory-Caregiver Distress Score (NPI-CDS) From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-3.6 score on a scale Standard Deviation 6.64	-6.6 score on a scale Standard Deviation 7.81	—
Change in the Total Neuropsychiatric Inventory-Caregiver Distress Score (NPI-CDS) From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-2.0 score on a scale Standard Deviation 5.74	-2.6 score on a scale Standard Deviation 5.52	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Populations. Data are 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. For the Agitation/Aggression domain, the caregiver is asked to rate how emotionally distressing they find the symptom behavior on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. A higher score represents increased distress. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the NPI-CDS for the Agitation/Aggression Domain From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-0.6 score on a scale Standard Deviation 1.32	-1.4 score on a scale Standard Deviation 1.54	—
Change in the NPI-CDS for the Agitation/Aggression Domain From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-0.7 score on a scale Standard Deviation 1.38	-0.5 score on a scale Standard Deviation 1.44	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Populations. Data are 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. For the NPI4D NPI-CDS score, the caregiver is asked to rate how emotionally distressing they find the symptom behavior (for the Agitation/Aggression, Irritability/Lability, Disinhibition, and Aberrant Motor Behavior domains) on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. The NPI4D NPI-CDS score ranges from 0 to 20. A higher score represents increased distress. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the NPI-CDS NPI4D Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-1.5 score on a scale Standard Deviation 3.39	-3.3 score on a scale Standard Deviation 4.11	—
Change in the NPI-CDS NPI4D Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-1.2 score on a scale Standard Deviation 3.08	-1.8 score on a scale Standard Deviation 3.12	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Populations. Data are 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. For the NPI4A NPI-CDS score, the caregiver is asked to rate how emotionally distressing they find the symptom behavior (for the Agitation/Aggression, Irritability/Lability, Anxiety, and Aberrant Motor Behavior domains) on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. The NPI4A NPI-CDS score ranges from 0 to 20. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the NPI-CDS NPI4A Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-1.7 score on a scale Standard Deviation 3.34	-3.3 score on a scale Standard Deviation 3.84	—
Change in the NPI-CDS NPI4A Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-1.0 score on a scale Standard Deviation 3.51	-1.5 score on a scale Standard Deviation 2.70	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

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

The CSI is a 13-question tool that is used to measure strain related to care provision and to identify families with potential caregiving concerns. There is at least one item for each of the following major domains: Employment, Financial, Physical, Social, and Time. A 0 (No) to 1 (Yes) scale is used for each of the 13 questions; thus the total score ranges from 0 to 13. Higher scores signify higher stress levels. Positive responses to 7 or more items on the index indicate a greater level of strain. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Caregiver Strain Index (CSI) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-0.6 score on a scale Standard Deviation 2.06	-1.2 score on a scale Standard Deviation 2.37	—
Change in the Caregiver Strain Index (CSI) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	0.1 score on a scale Standard Deviation 1.88	-0.2 score on a scale Standard Deviation 1.62	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

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

The CSDD is a 19-item interview specifically developed to assess the signs and symptoms of major depression in participants with dementia. Each of the 19 items is rated for severity on a scale of 0 to 2 (0, absent; 1, mild or intermittent; 2, severe). The total score is calculated as the sum of the item scores and thus ranges from 0 to 38. Higher scores signify more severe depression. Scores above 10 indicate probable major depression. Scores above 18 indicate definite major depression. Scores below 6, as a rule, are associated with the absence of significant depressive symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Cornell Scale for Depression in Dementia (CSDD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	0.6 score on a scale Standard Deviation 3.84	-1.0 score on a scale Standard Deviation 3.43	—
Change in the Cornell Scale for Depression in Dementia (CSDD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-0.7 score on a scale Standard Deviation 2.58	-0.9 score on a scale Standard Deviation 2.93	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

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

The MMSE is a brief test that is used to screen for cognitive impairment. The MMSE scale comprises 11 questions or simple tasks concerning orientation, memory, attention, and language to evaluate the participant's cognitive state. The anchor values are not consistent for each task. The MMSE total score is calculated by summing the item scores across all 11 tasks. A participant's total possible MMSE score ranges from 0 to 30 points. Higher scores indicate milder cognitive impairment. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Mini-Mental State Examination (MMSE) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline), as Analyzed by the Specified SPCD Methodology Day 70	-0.5 score on a scale Standard Deviation 2.53	0.3 score on a scale Standard Deviation 2.76	—
Change in the Mini-Mental State Examination (MMSE) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline), as Analyzed by the Specified SPCD Methodology Day 36	-0.3 score on a scale Standard Deviation 2.77	0.2 score on a scale Standard Deviation 3.02	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

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

The QoL-AD is a brief, 13-item measure designed specifically to obtain a rating of the participant's quality of life (QoL) from both the participant and the caregiver. It uses simple and straightforward language and responses and includes assessments of the individual's relationships with friends and family, concerns about finances, physical condition, mood, and an overall assessment of life quality. Caregivers complete the measure as a questionnaire about the participants' QoL, whereas participants complete it in interview format about their own QoL. Each of the 13 items is rated on a 4-point scale, with 1 indicating a poor QoL and 4 indicating an excellent QoL. Total scores range from 13 to 52, with a higher score indicating a better QoL. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Quality of Life-Alzheimer's Disease (QoL-AD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Cargiver	0.3 score on a scale Standard Deviation 4.66	0.4 score on a scale Standard Deviation 4.28	—
Change in the Quality of Life-Alzheimer's Disease (QoL-AD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Caregiver	0.9 score on a scale Standard Deviation 4.27	-0.3 score on a scale Standard Deviation 3.93	—
Change in the Quality of Life-Alzheimer's Disease (QoL-AD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36, Participant	-0.0 score on a scale Standard Deviation 5.18	1.3 score on a scale Standard Deviation 6.12	—
Change in the Quality of Life-Alzheimer's Disease (QoL-AD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70, Participant	0.7 score on a scale Standard Deviation 4.26	1.5 score on a scale Standard Deviation 5.06	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

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

The ADCS-ADL inventory measures basic activities of daily living such as dressing, conversation, eating, bathing, and grooming. The 19-item version, covering mainly basic ADL, is used to assess participants with more severe disabilities. The ADCS-ADL uses a scale from 0 to 54. Lower scores indicate declining ability. Change from Baseline is calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 70	-0.6 score on a scale Standard Deviation 3.45	-2.0 score on a scale Standard Deviation 4.64	—
Change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 Day 36	-0.8 score on a scale Standard Deviation 3.89	-0.9 score on a scale Standard Deviation 4.27	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Days 8 and 22; Day 36 (Stage 2 Baseline); Days 43 and 57

Population: Stage 1 and Stage 2 mITT Populations. Data are 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 was designed to collect information on the behavioral aspects of agitation/aggression in participants with probable AD and clinically meaningful agitation secondary to AD. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, marked. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Placebo n=124 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=93 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Change in the NPI Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 8 and Day 22 and From Day 36 (Stage 2 Baseline) to Day 43 and Day 57 Day 8	-1.4 score on a scale Standard Deviation 2.73	-2.2 score on a scale Standard Deviation 2.93	—
Change in the NPI Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 8 and Day 22 and From Day 36 (Stage 2 Baseline) to Day 43 and Day 57 Day 22	-1.6 score on a scale Standard Deviation 2.86	-2.7 score on a scale Standard Deviation 3.18	—
Change in the NPI Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 8 and Day 22 and From Day 36 (Stage 2 Baseline) to Day 43 and Day 57 Day 43	-1.3 score on a scale Standard Deviation 2.92	-0.5 score on a scale Standard Deviation 2.31	—
Change in the NPI Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 8 and Day 22 and From Day 36 (Stage 2 Baseline) to Day 43 and Day 57 Day 57	-1.3 score on a scale Standard Deviation 2.86	-1.2 score on a scale Standard Deviation 3.12	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

Population: Stage 1 and Stage 2 mITT Populations. Data are 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 participant is 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 is defined as the last non-missing assessment prior to Stage 1 randomization.

Outcome measures

Outcome measures
Measure	Placebo n=123 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=88 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Marked improvement	1 participants	8 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Moderate improvement	13 participants	22 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, No change	48 participants	22 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Marked worsening	9 participants	3 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Moderate worsening	0 participants	3 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Minimal improvement	43 participants	28 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Minimal worsening	12 participants	7 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Moderate worsening	6 participants	1 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Marked worsening	0 participants	0 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Marked improvement	4 participants	4 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Moderate improvement	5 participants	10 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Minimal improvement	11 participants	10 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, No change	14 participants	12 participants	—
Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Minimal worsening	1 participants	0 participants	—

SECONDARY outcome

Timeframe: Day 36 (Stage 2 Baseline); Day 70

Population: Stage 2 mITT Population. Data are 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 participant is 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. For placebo non-responders re-randomized to AVP-923 or placebo at Stage 2, Baseline is defined as the last non-missing assessment prior to Stage 2 re-randomization.

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=42 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) Moderate worsening	2 participants	1 participants	—
Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) Marked improvement	4 participants	0 participants	—
Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) Moderate improvement	2 participants	11 participants	—
Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) Minimal improvement	8 participants	15 participants	—
Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) No change	19 participants	11 participants	—
Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) Marked worsening	6 participants	4 participants	—
Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) Minimal worsening	1 participants	0 participants	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70

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

The PGI-C uses a 7-point scale to assess treatment response and to rate the global impression of clinical change in a participant's agitation. The participant is asked to rate their impression of change from Baseline as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse. Baseline is defined as the last non-missing assessment prior to Stage 1 randomization.

Outcome measures

Outcome measures
Measure	Placebo n=123 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=88 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Minimally improved	30 participants	20 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Minimally improved	11 participants	14 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, No change	13 participants	10 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Very much improved	2 participants	10 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Much improved	23 participants	24 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, No change	40 participants	20 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Minimally worse	23 participants	13 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Much worse	4 participants	1 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 36, Very much worse	1 participants	0 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Very much improved	3 participants	3 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Much improved	4 participants	10 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Minimally worse	9 participants	4 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Much worse	4 participants	2 participants	—
Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Day 70, Very much worse	0 participants	0 participants	—

SECONDARY outcome

Timeframe: Day 1 (Stage 1 Baseline); Day 70

Population: Only AVP-923/only placebo ITT Subset

The PGI-C uses a 7-point scale to assess treatment response and to rate the global impression of clinical change in a participant's agitation. The participant is asked to rate their impression of change from Baseline as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse. For placebo non-responders re-randomized to AVP-923 or placebo at Stage 2, Baseline is defined as the last non-missing assessment prior to Stage 2 re-randomization.

Outcome measures

Outcome measures
Measure	Placebo n=59 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=81 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Very much improved	5 participants	9 participants	—
Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Much improved	9 participants	26 participants	—
Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Very much worse	0 participants	0 participants	—
Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Minimally improved	17 participants	25 participants	—
Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) No change	14 participants	13 participants	—
Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Minimally worse	10 participants	5 participants	—
Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) Much worse	4 participants	3 participants	—

SECONDARY outcome

Timeframe: up to Week 10

Population: mITT Population: all participants randomized in Stage 1 who had at least one post-Baseline NPI Agitation/Aggression score in Stage 1, and all placebo non-responders from Stage 1 who are re-randomized in Stage 2 and had at least one post-Week 4 NPI Agitation/Aggression score in Stage 2. Only those participants who took CMs were analyzed.

Concomitant medications (CMs) are defined as non-study medications with a start date on or before the final study visit, and that were either ongoing at the end of the study or had a stop date on or after the date of first dose of study drug. Drugs for the treatment of AD (e.g., donepezil, rivastigmine, galantamine, memantine) were allowed when administered at stable dose for at least 2 months prior to randomization. Concomitant use of the following medications was allowed, provided the participant had been on a stable dose for at least 1 month prior to randomization and remained stable throughout the study: medications for agitation secondary to AD; medications for nighttime management of insomnia or behavioral disturbances that included short-acting benzodiazepines, a low dose of alprazolam up to 0.5 milligrams (mg)/day, and a low dose of trazodone up to 50 mg/day; hypnotics for the treatment of insomnia; and certain classes of antidepressants.

Outcome measures

Outcome measures
Measure	Placebo n=84 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=53 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 n=58 Participants Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Number of Participants With the Indicated Change in the Concomitant Use of Allowed Psychotropic Drugs Compared to Their Baseline Use Dose reduced	1 participants	0 participants	1 participants
Number of Participants With the Indicated Change in the Concomitant Use of Allowed Psychotropic Drugs Compared to Their Baseline Use Change in frequency	1 participants	1 participants	1 participants
Number of Participants With the Indicated Change in the Concomitant Use of Allowed Psychotropic Drugs Compared to Their Baseline Use New usage	7 participants	6 participants	11 participants
Number of Participants With the Indicated Change in the Concomitant Use of Allowed Psychotropic Drugs Compared to Their Baseline Use Any change	9 participants	8 participants	13 participants
Number of Participants With the Indicated Change in the Concomitant Use of Allowed Psychotropic Drugs Compared to Their Baseline Use Dose increased	0 participants	1 participants	1 participants
Number of Participants With the Indicated Change in the Concomitant Use of Allowed Psychotropic Drugs Compared to Their Baseline Use Use discontinued	2 participants	2 participants	2 participants

SECONDARY outcome

Timeframe: up to Week 10

Population: mITT Population

Participants were allowed to receive oral lorazepam as rescue medication for the short-term treatment of symptoms of agitation, if deemed necessary by the investigator. Lorazepam was to be administered at doses up to 1.5 mg/day, and dosing was not to exceed 3 days in any 7-day period.

Outcome measures

Outcome measures
Measure	Placebo n=93 Participants All participants randomized to receive placebo in Stage 1, and all placebo non-responders re-randomized at Stage 2 to placebo	AVP-923 n=59 Participants All participants randomized to receive AVP-923 in Stage 1, and all placebo non-responders re-randomized at Stage 2 to AVP-923.	Placebo in Stage 1/Placebo in Stage 2 n=66 Participants Participants receive matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Number of Participants Using Rescue Medications Overall	5 participants	11 participants	7 participants
Number of Participants Using Rescue Medications Day 57 (Visit 6)	1 participants	3 participants	4 participants
Number of Participants Using Rescue Medications Day 70 (Visit 70)	2 participants	3 participants	3 participants
Number of Participants Using Rescue Medications Day 8 (Visit 2)	0 participants	3 participants	1 participants
Number of Participants Using Rescue Medications Day 22 (Visit 3)	3 participants	3 participants	3 participants
Number of Participants Using Rescue Medications Day 36 (Visit 4)	5 participants	3 participants	3 participants
Number of Participants Using Rescue Medications Day 43 (Visit 5)	2 participants	3 participants	5 participants

Adverse Events

AVP-923 in Stage 1/AVP-923 in Stage 2

Serious events: 9 serious events

Other events: 24 other events

Deaths: 0 deaths

Placebo in Stage 1/AVP-923 in Stage 2

Serious events: 3 serious events

Other events: 12 other events

Deaths: 0 deaths

Placebo in Stage 1/Placebo in Stage 2

Serious events: 6 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	AVP-923 in Stage 1/AVP-923 in Stage 2 n=93 participants at risk Participants received oral AVP-923 during Stage 1 for 5 consecutive weeks. Participants received AVP-923-20 once daily (QD) in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 1 (Days 1 to 7), AVP-923-20 twice a day (BID) during the next 2 consecutive weeks (Days 8 to 21), and AVP-923-30 BID during the final 2 weeks of Stage 1 (Days 22 to 35). Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants continued to receive AVP-923-30 BID for the entire 5-week duration of Stage 2. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 2 (Days 36 to 42), AVP-923-20 BID during the next 2 consecutive weeks (Days 43 to 56), and AVP-923-30 BID during the final 2 weeks of Stage 2 (Days 57 to 70).	Placebo in Stage 1/AVP-923 in Stage 2 n=59 participants at risk Participants received matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive AVP-923 in Stage 2. Participants received AVP-923-20 QD in the morning and placebo in the evening (to maintain the blind) during the first week of Stage 2 (Days 36 to 42), AVP-923-20 BID during the next 2 consecutive weeks (Days 43 to 56), and AVP-923-30 BID during the final 2 weeks of Stage 2 (Days 57 to 70).	Placebo in Stage 1/Placebo in Stage 2 n=68 participants at risk Participants received matching oral placebo during Stage 1 for 5 consecutive weeks. Participants who completed Stage 1 were eligible to participate in Stage 2 of the study. Participants who were randomized to placebo in Stage 1 were stratified (based on their clinical response during Stage 1) into two subgroups (responders or non-responders) and were re-randomized to receive matching placebo BID throughout Stage 2.
Gastrointestinal disorders Diarrhoea	5.4% 5/93 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	6.8% 4/59 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	5.9% 4/68 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.
Infections and infestations Urinary Tract Infection	5.4% 5/93 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	5.1% 3/59 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	5.9% 4/68 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Fall	10.8% 10/93 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	5.1% 3/59 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	5.9% 4/68 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/93 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	5.1% 3/59 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	1.5% 1/68 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.
Nervous system disorders Dizziness	6.5% 6/93 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	1.7% 1/59 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	2.9% 2/68 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.
Psychiatric disorders Agitation	3.2% 3/93 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	1.7% 1/59 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.	7.4% 5/68 • up to Week 10 Treatment-emergent adverse events (TEAEs), defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days), are reported. TEAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study treatment.

Additional Information

Avanir Medical Information

Avanir Pharmaceuticals, Inc.

Phone: 855-572-2722

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER