Trial Outcomes & Findings for Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Residual Schizophrenia (NCT NCT02477670)

Last Updated: 2020-09-16

Results Overview

The NSA-16 is a measure of the presence, severity, and range of negative symptoms associated with schizophrenia. It has a high interrater and test-retest reliability across languages and cultures. The NSA-16 uses a 5-factor model to describe negative symptoms: (1) communication, (2) emotion/affect, (3) social involvement, (4) motivation, and (5) retardation. The possible NSA-16 total score ranges from 16 to 96, with a higher score indicating a worse condition. Change was Baseline was calculated as the post-Baseline value minus the Baseline value.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

145 participants

Primary outcome timeframe

Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Results posted on

2020-09-16

Participant Flow

Of the 145 participants randomized at the beginning of the study, 127 patients met the criteria for the Modified Intent-to-Treat (mITT) Population and were included in the Stage 1 mITT Population. A total of 108 participants were included in the Stage 2 mITT Population.

Participant Flow data are reported for members of the mITT Population. Stage 1: participants randomized in Stage 1 who had at least 1 post-baseline NSA-16 total score assessment in Stage 1. Stage 2: participants who were re-randomized into Stage 2 and had at least 1 NSA-16 total score assessment in Stage 2 (after Week 6).

Participant milestones

Participant milestones
Measure	Stage 1: AVP-786 Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Stage 1 STARTED	47	80	0	0	0	0	0
Stage 1 COMPLETED	43	67	0	0	0	0	0
Stage 1 NOT COMPLETED	4	13	0	0	0	0	0
Stage 2 STARTED	0	0	30	33	2	1	42
Stage 2 COMPLETED	0	0	28	32	2	1	42
Stage 2 NOT COMPLETED	0	0	2	1	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Stage 1: AVP-786 Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.
Stage 1 Adverse Event	2	7	0	0
Stage 1 Lost to Follow-up	0	2	0	0
Stage 1 Withdrawal by Subject	1	2	0	0
Stage 1 Non-compliance with Study Drug	1	2	0	0
Stage 2 Adverse Event	0	0	1	0
Stage 2 Antipsychotic Medication Changed	0	0	1	0
Stage 2 Withdrawal by Subject	0	0	0	1

Baseline Characteristics

Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Residual Schizophrenia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=96 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally twice a day (BID) in Stage 1.	AVP-786 n=48 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days in Stage 1. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID).	Total n=144 Participants Total of all reporting groups
Age, Continuous	44.9 Years STANDARD_DEVIATION 10.83 • n=5 Participants	46.5 Years STANDARD_DEVIATION 12.04 • n=7 Participants	45.4 Years STANDARD_DEVIATION 11.23 • n=5 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	18 Participants n=7 Participants	45 Participants n=5 Participants
Sex: Female, Male Male	69 Participants n=5 Participants	30 Participants n=7 Participants	99 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	12 Participants n=5 Participants	4 Participants n=7 Participants	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	84 Participants n=5 Participants	44 Participants n=7 Participants	128 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 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	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 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
Race (NIH/OMB) Black or African American	53 Participants n=5 Participants	25 Participants n=7 Participants	78 Participants n=5 Participants
Race (NIH/OMB) White	36 Participants n=5 Participants	18 Participants n=7 Participants	54 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	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

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

Population: Modified Intent-To-Treat (mITT) Population. Stage 1: randomized participants who had at least 1 post-Baseline NSA-16 total score assessment in Stage 1. Stage 2 (Stage 1 Placebo Non-responders): re-randomized participants who had at least 1 NSA-16 total score assessment in Stage 2. Only those participants with available data were analyzed.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the 16-Item Negative Symptom Assessment (NSA-16) Total Score at Week 6 and Week 12 Stage 1 Baseline	61.0 score on a scale Standard Deviation 7.53	60.4 score on a scale Standard Deviation 7.71	—	—	—	—	—
Change From Baseline in the 16-Item Negative Symptom Assessment (NSA-16) Total Score at Week 6 and Week 12 Change from Baseline at Week 6	-5.0 score on a scale Standard Deviation 5.64	-3.4 score on a scale Standard Deviation 5.54	—	—	—	—	—
Change From Baseline in the 16-Item Negative Symptom Assessment (NSA-16) Total Score at Week 6 and Week 12 Stage 2 Baseline	—	—	57.6 score on a scale Standard Deviation 9.39	57.6 score on a scale Standard Deviation 9.09	—	—	—
Change From Baseline in the 16-Item Negative Symptom Assessment (NSA-16) Total Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-2.4 score on a scale Standard Deviation 5.88	-3.7 score on a scale Standard Deviation 6.41	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The PANSS is a 30-item clinical scale that is extensively used as a reliable and valid measure for negative symptom trials. The PANNS consists of 6 subscales: positive subscale; negative subscale; general psychopathology subscale; prosocial factors (active social avoidance, emotional withdrawal, passive/apathetic social withdrawal, stereotyped thinking, hallucinatory behavior, suspiciousness/persecution); Marder negative factors (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity and flow of conversation, motor retardation, active social avoidance); excitement component (excitement, hostility, tension, uncooperativeness, poor impulse control). Each item was scored from "1" (absent) to "7" (extremely severe). The PANSS total score ranges from 30 to 210, with a higher score indicating greater severity of symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 and Week 12 Stage 1 Baseline	67.4 score on a scale Standard Deviation 8.26	68.7 score on a scale Standard Deviation 7.99	—	—	—	—	—
Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 and Week 12 Change from Baseline at Week 6	-4.7 score on a scale Standard Deviation 6.98	-2.5 score on a scale Standard Deviation 6.50	—	—	—	—	—
Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 and Week 12 Stage 2 Baseline	—	—	67.1 score on a scale Standard Deviation 9.00	65.6 score on a scale Standard Deviation 8.07	—	—	—
Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-1.4 score on a scale Standard Deviation 7.64	-4.0 score on a scale Standard Deviation 7.71	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The negative subscale includes items N1 - N7 in the PANSS. Each item was scored from "1" (absent) to "7" (extremely severe). The score ranges from 7 to 49, with higher scores indicative of greater severity of the negative symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the PANSS Negative Subscale Score at Week 6 and Week 12 Stage 1 Baseline	24.6 score on a scale Standard Deviation 3.51	25.2 score on a scale Standard Deviation 3.64	—	—	—	—	—
Change From Baseline in the PANSS Negative Subscale Score at Week 6 and Week 12 Change from Baseline at Week 6	-2.2 score on a scale Standard Deviation 3.33	-1.5 score on a scale Standard Deviation 3.81	—	—	—	—	—
Change From Baseline in the PANSS Negative Subscale Score at Week 6 and Week 12 Stage 2 Baseline	—	—	24.4 score on a scale Standard Deviation 4.55	23.6 score on a scale Standard Deviation 4.53	—	—	—
Change From Baseline in the PANSS Negative Subscale Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-1.0 score on a scale Standard Deviation 2.69	-2.3 score on a scale Standard Deviation 3.12	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The Marder negative factors comprise 7 items of the PANSS: N1 (blunted affect); N2 (emotional withdrawal); N3 (poor rapport); N4 (passive/apathetic social withdrawal); N6 (lack of spontaneity and flow of conversation); G7 (motor retardation), and G16 (active social avoidance). Each item is scored from "1" (absent) to "7" (extremely severe). The score ranges from 7 to 49, with higher scores indicative of greater severity of the negative symptoms of schizophrenia. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the PANSS Marder Negative Factor Score at Week 6 and Week 12 Stage 1 Baseline	24.1 score on a scale Standard Deviation 4.24	24.2 score on a scale Standard Deviation 3.81	—	—	—	—	—
Change From Baseline in the PANSS Marder Negative Factor Score at Week 6 and Week 12 Change from Baseline at Week 6	-2.1 score on a scale Standard Deviation 3.34	-1.6 score on a scale Standard Deviation 3.48	—	—	—	—	—
Change From Baseline in the PANSS Marder Negative Factor Score at Week 6 and Week 12 Stage 2 Baseline	—	—	23.0 score on a scale Standard Deviation 4.62	22.3 score on a scale Standard Deviation 5.45	—	—	—
Change From Baseline in the PANSS Marder Negative Factor Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.8 score on a scale Standard Deviation 2.80	-2.5 score on a scale Standard Deviation 4.27	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The prosocial factors include items: G16 (active social avoidance); N2 (emotional withdrawal); N4 (passive/apathetic social withdrawal); N7 (stereotyped thinking); P3 (hallucinatory behavior); and P6 (suspiciousness/persecution) in the PANSS. Each item was scored from "1" (absent) to "7" (extremely severe). The score ranges from 6 to 42, with higher scores indicative of greater severity of the specific negative symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the PANSS Prosocial Factor Subscale Score at Week 6 at Week 12 Stage 1 Baseline	18.3 score on a scale Standard Deviation 3.24	18.4 score on a scale Standard Deviation 2.92	—	—	—	—	—
Change From Baseline in the PANSS Prosocial Factor Subscale Score at Week 6 at Week 12 Change from Baseline at Week 6	-2.0 score on a scale Standard Deviation 2.18	-1.1 score on a scale Standard Deviation 2.53	—	—	—	—	—
Change From Baseline in the PANSS Prosocial Factor Subscale Score at Week 6 at Week 12 Stage 2 Baseline	—	—	17.7 score on a scale Standard Deviation 3.27	17.0 score on a scale Standard Deviation 3.30	—	—	—
Change From Baseline in the PANSS Prosocial Factor Subscale Score at Week 6 at Week 12 Change from Baseline at Week 12	—	—	-0.7 score on a scale Standard Deviation 2.02	-1.4 score on a scale Standard Deviation 2.35	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The positive subscale includes items P1 - P7 in the PANSS. Each item is scored from "1" (absent) to "7" (extremely severe). The score ranges from 7 to 49, with higher scores indicative of greater severity of the positive symptoms of schizophrenia. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the PANSS Positive Subscale Score at Week 6 and Week 12 Stage 1 Baseline	13.6 score on a scale Standard Deviation 3.65	13.4 score on a scale Standard Deviation 2.81	—	—	—	—	—
Change From Baseline in the PANSS Positive Subscale Score at Week 6 and Week 12 Change from Baseline at Week 6	-0.8 score on a scale Standard Deviation 2.63	-0.3 score on a scale Standard Deviation 2.57	—	—	—	—	—
Change From Baseline in the PANSS Positive Subscale Score at Week 6 and Week 12 Stage 2 Baseline	—	—	13.1 score on a scale Standard Deviation 3.64	13.3 score on a scale Standard Deviation 3.39	—	—	—
Change From Baseline in the PANSS Positive Subscale Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.4 score on a scale Standard Deviation 1.99	-0.3 score on a scale Standard Deviation 2.47	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The general psychopathology subscale includes items G1 - G16 in the PANSS. Each item was scored from "1" (absent) to "7" (extremely severe). The score ranges from 16 to 112, with higher scores indicative of greater severity of symptoms of schizophrenia. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the PANSS General Psychopathology Subscale Score at Week 6 and Week 12 Stage 1 Baseline	29.1 score on a scale Standard Deviation 4.66	30.1 score on a scale Standard Deviation 5.05	—	—	—	—	—
Change From Baseline in the PANSS General Psychopathology Subscale Score at Week 6 and Week 12 Change from Baseline at Week 6	-1.7 score on a scale Standard Deviation 4.04	-0.7 score on a scale Standard Deviation 3.21	—	—	—	—	—
Change From Baseline in the PANSS General Psychopathology Subscale Score at Week 6 and Week 12 Stage 2 Baseline	—	—	29.7 score on a scale Standard Deviation 5.40	28.7 score on a scale Standard Deviation 4.84	—	—	—
Change From Baseline in the PANSS General Psychopathology Subscale Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	0.0 score on a scale Standard Deviation 5.14	-1.3 score on a scale Standard Deviation 5.10	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The excitement component includes items: P4 (excitement); P7 (hostility); G4 (tension); G8 (uncooperativeness); and G14 (poor impulse control). Each item is scored from "1" (absent) to "7" (extremely severe). The score ranges from 5 to 35, with higher scores indicative of greater severity of symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the PANSS Excitement Component Subscale Score at Week 6 and Week 12 Stage 1 Baseline	6.2 score on a scale Standard Deviation 1.57	6.3 score on a scale Standard Deviation 2.10	—	—	—	—	—
Change From Baseline in the PANSS Excitement Component Subscale Score at Week 6 and Week 12 Change from Baseline at Week 6	-0.4 score on a scale Standard Deviation 1.64	-0.2 score on a scale Standard Deviation 1.57	—	—	—	—	—
Change From Baseline in the PANSS Excitement Component Subscale Score at Week 6 and Week 12 Stage 2 Baseline	—	—	5.8 score on a scale Standard Deviation 1.27	6.7 score on a scale Standard Deviation 2.59	—	—	—
Change From Baseline in the PANSS Excitement Component Subscale Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	0.0 score on a scale Standard Deviation 2.04	-0.1 score on a scale Standard Deviation 1.77	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

NSA-16 Communication Factor Domain scores range from 4 to 24, with higher scores indicating greater clinical severity of symptoms. Negative values indicate improvement. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the NSA-16 Communication Domain Score at Week 6 and Week 12 Stage 1 Baseline	12.5 score on a scale Standard Deviation 2.54	12.6 score on a scale Standard Deviation 2.71	—	—	—	—	—
Change From Baseline in the NSA-16 Communication Domain Score at Week 6 and Week 12 Change from Baseline at Week 6	-1.3 score on a scale Standard Deviation 2.32	-1.0 score on a scale Standard Deviation 1.91	—	—	—	—	—
Change From Baseline in the NSA-16 Communication Domain Score at Week 6 and Week 12 Stage 2 Baseline	—	—	12.0 score on a scale Standard Deviation 2.98	11.8 score on a scale Standard Deviation 3.12	—	—	—
Change From Baseline in the NSA-16 Communication Domain Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.4 score on a scale Standard Deviation 1.86	-1.0 score on a scale Standard Deviation 1.56	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

NSA-16 Emotion/Affect Domain scores range from 3 to 18, with higher scores indicating a greater clinical severity of symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the NSA-16 Emotion/Affect Domain Score at Week 6 and Week 12 Stage 1 Baseline	12.6 score on a scale Standard Deviation 2.11	12.2 score on a scale Standard Deviation 1.81	—	—	—	—	—
Change From Baseline in the NSA-16 Emotion/Affect Domain Score at Week 6 and Week 12 Change from Baseline at Week 6	-1.0 score on a scale Standard Deviation 1.28	-0.6 score on a scale Standard Deviation 1.54	—	—	—	—	—
Change From Baseline in the NSA-16 Emotion/Affect Domain Score at Week 6 and Week 12 Stage 2 Baseline	—	—	11.7 score on a scale Standard Deviation 1.84	11.7 score on a scale Standard Deviation 2.09	—	—	—
Change From Baseline in the NSA-16 Emotion/Affect Domain Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.4 score on a scale Standard Deviation 1.50	-0.6 score on a scale Standard Deviation 1.36	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

NSA-16 Social Involvement Factor Domain scores range from 3 to 18, with higher scores indicating greater clinical severity of symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the NSA-16 Social Involvement Domain Score at Week 6 and Week 12 Stage 1 Baseline	12.2 score on a scale Standard Deviation 2.02	12.2 score on a scale Standard Deviation 2.20	—	—	—	—	—
Change From Baseline in the NSA-16 Social Involvement Domain Score at Week 6 and Week 12 Change from Baseline at Week 6	-0.6 score on a scale Standard Deviation 1.87	-0.3 score on a scale Standard Deviation 1.92	—	—	—	—	—
Change From Baseline in the NSA-16 Social Involvement Domain Score at Week 6 and Week 12 Stage 2 Baseline	—	—	12.1 score on a scale Standard Deviation 2.12	12.0 score on a scale Standard Deviation 2.56	—	—	—
Change From Baseline in the NSA-16 Social Involvement Domain Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.8 score on a scale Standard Deviation 1.40	-1.1 score on a scale Standard Deviation 2.51	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

NSA-16 Motivation Factor Domain scores range from 4 to 24, with higher scores indicating greater clinical severity of symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the NSA-16 Motivation Domain Score at Week 6 and Week 12 Stage 1 Baseline	16.5 score on a scale Standard Deviation 2.37	16.7 score on a scale Standard Deviation 2.33	—	—	—	—	—
Change From Baseline in the NSA-16 Motivation Domain Score at Week 6 and Week 12 Change from Baseline at Week 6	-1.4 score on a scale Standard Deviation 1.96	-0.9 score on a scale Standard Deviation 1.80	—	—	—	—	—
Change From Baseline in the NSA-16 Motivation Domain Score at Week 6 and Week 12 Stage 2 Baseline	—	—	15.8 score on a scale Standard Deviation 2.61	15.8 score on a scale Standard Deviation 2.39	—	—	—
Change From Baseline in the NSA-16 Motivation Domain Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.4 score on a scale Standard Deviation 2.13	-0.4 score on a scale Standard Deviation 2.09	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

NSA-16 Retardation Factor Domain scores range from 3 to 18, with higher scores indicating greater clinical severity of symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the NSA-16 Retardation Domain Score at Week 6 at Week 12 Stage 1 Baseline	7.2 score on a scale Standard Deviation 1.54	6.7 score on a scale Standard Deviation 1.61	—	—	—	—	—
Change From Baseline in the NSA-16 Retardation Domain Score at Week 6 at Week 12 Change from Baseline at Week 6	-0.8 score on a scale Standard Deviation 1.46	-0.6 score on a scale Standard Deviation 1.20	—	—	—	—	—
Change From Baseline in the NSA-16 Retardation Domain Score at Week 6 at Week 12 Stage 2 Baseline	—	—	6.0 score on a scale Standard Deviation 2.00	6.3 score on a scale Standard Deviation 2.05	—	—	—
Change From Baseline in the NSA-16 Retardation Domain Score at Week 6 at Week 12 Change from Baseline at Week 12	—	—	-0.3 score on a scale Standard Deviation 1.20	-0.5 score on a scale Standard Deviation 1.81	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The global negative symptoms rating in the NSA-16 is a single score based on the overall impression of severity of negative symptoms on a 1 to 7 scale, where higher scores indicate greater severity. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the NSA-16 Global Negative Symptoms Score at Week 6 and Week 12 Stage 1 Baseline	4.6 score on a scale Standard Deviation 0.64	4.6 score on a scale Standard Deviation 0.61	—	—	—	—	—
Change From Baseline in the NSA-16 Global Negative Symptoms Score at Week 6 and Week 12 Change from Baseline at Week 6	-0.4 score on a scale Standard Deviation 0.68	-0.2 score on a scale Standard Deviation 0.64	—	—	—	—	—
Change From Baseline in the NSA-16 Global Negative Symptoms Score at Week 6 and Week 12 Stage 2 Baseline	—	—	4.3 score on a scale Standard Deviation 0.71	4.4 score on a scale Standard Deviation 0.75	—	—	—
Change From Baseline in the NSA-16 Global Negative Symptoms Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.1 score on a scale Standard Deviation 0.51	-0.5 score on a scale Standard Deviation 0.75	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The global level of functioning is a single score on a scale of 1 to 7 that provides the overall assessment of the participant's level of functioning, with higher scores indicative of severe impairment in functioning. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=46 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=29 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the NSA-16 Global Level of Functioning Score at Week 6 and Week 12 Stage 1 Baseline	4.7 score on a scale Standard Deviation 0.73	4.6 score on a scale Standard Deviation 0.63	—	—	—	—	—
Change From Baseline in the NSA-16 Global Level of Functioning Score at Week 6 and Week 12 Change from Baseline at Week 6	-0.4 score on a scale Standard Deviation 0.61	-0.2 score on a scale Standard Deviation 0.55	—	—	—	—	—
Change From Baseline in the NSA-16 Global Level of Functioning Score at Week 6 and Week 12 Stage 2 Baseline	—	—	4.5 score on a scale Standard Deviation 0.74	4.4 score on a scale Standard Deviation 0.70	—	—	—
Change From Baseline in the NSA-16 Global Level of Functioning Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.3 score on a scale Standard Deviation 0.52	-0.3 score on a scale Standard Deviation 0.64	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The MCCB is the standard tool for assessing cognitive change in trials of cognitive-enhancing agents in schizophrenia and is used to provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia and related disorders. It is made up of 10 tests that measure 7 cognitive domains: Speed of Processing; Attention/Vigilance; Working Memory; Verbal Learning; Visual Learning; Reasoning and Problem Solving; and Social Cognition. The MCCB was to be conducted at approximately the same time of day (+/- 2 hours) and preferably in the morning. The MCCB composite score ranges from 0 to 70, with higher scores indicative of less severe cognition symptoms. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score at Week 6 and Week 12 Stage 1 Baseline	32.5 score on a scale Standard Deviation 11.37	28.8 score on a scale Standard Deviation 13.09	—	—	—	—	—
Change From Baseline in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score at Week 6 and Week 12 Change from Baseline at Week 6	1.2 score on a scale Standard Deviation 5.11	1.6 score on a scale Standard Deviation 4.55	—	—	—	—	—
Change From Baseline in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score at Week 6 and Week 12 Stage 2 Baseline	—	—	31.7 score on a scale Standard Deviation 14.99	28.9 score on a scale Standard Deviation 10.69	—	—	—
Change From Baseline in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-1.6 score on a scale Standard Deviation 4.06	1.6 score on a scale Standard Deviation 3.71	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The CGI is an assessment of a participant's global functioning prior to and after initiating study medication and provides an overall clinician-determined summary measure that takes into account knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. It is based on a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. Considering the total clinical experience, a participant is assessed on severity of mental illness at the time of rating: 1 (normal, not at all ill); 2 (borderline mentally ill); 3 (mildly ill); 4 (moderately ill); 5 (markedly ill); 6 (severely ill); or 7 (among the most extremely ill participants). Scores range from 1 to 7, with higher scores indicative of greater severity of illness.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=46 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=78 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=31 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Mean Actual Clinical Global Impression of Severity (CGI-S) of Illness Score at Week 6 and Week 12 Week 6	3.6 score on a scale Standard Deviation 0.80	3.8 score on a scale Standard Deviation 0.77	—	—	—	—	—
Mean Actual Clinical Global Impression of Severity (CGI-S) of Illness Score at Week 6 and Week 12 Week 12	—	—	3.7 score on a scale Standard Deviation 0.75	3.5 score on a scale Standard Deviation 0.93	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed. Week 6 scores are relative to Stage 1 Baseline. Week 12 scores are relative to Week 6.

The CGI is an assessment of the participant's global functioning prior to and after initiating a study medication and provides an overall clinician-determined summary measure that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. It is based on a 7-point scale that requires the clinician to rate the change of the participant's condition at the time of assessment, relative to the clinician's past experience with the participant's condition at admission. Considering the total clinical experienced, a participant is assessed for change of mental illness as: 1 (very much improved); 2 (much improved); 3 (minimally improved); 4 (no change); 5 (minimally worse); 6 (much worse); or 7 (very much worse). Scores range from 1 to 7, with higher scores indicative of greater severity of illness.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=78 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=32 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Mean Actual Clinical Global Impression of Change (CGI-C) Score at Week 6 and Week 12 Week 6	3.4 score on a scale Standard Deviation 0.80	3.6 score on a scale Standard Deviation 0.69	—	—	—	—	—
Mean Actual Clinical Global Impression of Change (CGI-C) Score at Week 6 and Week 12 Week 12	—	—	3.8 score on a scale Standard Deviation 0.90	3.5 score on a scale Standard Deviation 0.80	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The PGI-C is a 7-point, participant-rated scale used to assess treatment response as: 0=Not assessed; 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally 6=worse; or 7=very much worse. Week 6 and Week 12 scores are relative to Stage 1 Baseline.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=75 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=32 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Mean Actual Patient Global Impression of Change (PGI-C) Score at Week 6 at Week 12 Week 6	3.1 score on a scale Standard Deviation 0.94	3.2 score on a scale Standard Deviation 1.01	—	—	—	—	—
Mean Actual Patient Global Impression of Change (PGI-C) Score at Week 6 at Week 12 Week 12	—	—	3.3 score on a scale Standard Deviation 0.78	2.9 score on a scale Standard Deviation 1.11	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The CDSS is a 9-item scale derived from the Hamilton Depression Scale (Ham-D) that is designed to assess depression specifically in participants with schizophrenia. Unlike the Ham-D, the CDSS does not contain depressive symptoms that overlap with negative symptoms of schizophrenia, such as anhedonia and social withdrawal. Each item on the scale is scored as: 0 (absent); 1 (mild); 2 (moderate); or 3 (severe). The CDSS is obtained by adding each of the item scores. A score above 6 has an 82% specificity and 85% sensitivity for predicting the presence of a major depressive episode. The CDSS score ranges from 0 to 27, with higher scores indicative of severe symptoms of depression. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) Total Score at Week 6 and Week 12 Stage 1 Baseline	1.1 score on a scale Standard Deviation 1.34	0.9 score on a scale Standard Deviation 1.31	—	—	—	—	—
Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) Total Score at Week 6 and Week 12 Chane from Baseline at Week 6	-0.2 score on a scale Standard Deviation 1.34	-0.1 score on a scale Standard Deviation 1.02	—	—	—	—	—
Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) Total Score at Week 6 and Week 12 Stage 2 Baseline	—	—	1.0 score on a scale Standard Deviation 1.56	0.8 score on a scale Standard Deviation 1.54	—	—	—
Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) Total Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.4 score on a scale Standard Deviation 1.24	-0.0 score on a scale Standard Deviation 1.66	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized task in which participants are given the opportunity on each trial to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. The test measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. The ratio of hard task choices with moderate probability reward is used as an outcome measure for negative symptoms. EEfRT scores are analyzed for 8 variables. Variable 1 is the Baseline press rate and is defined as the value coded as average presses/second. Scores range from 0 to 9, with higher scores indicative of faster button pressing ability. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=66 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=18 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the Effort Expenditure for Reward Task (EEfRT) Score for Baseline Press Rate at Week 6 and Week 12 Stage 1 Baseline	3.39 score on a scale Standard Deviation 1.137	3.39 score on a scale Standard Deviation 1.112	—	—	—	—	—
Change From Baseline in the Effort Expenditure for Reward Task (EEfRT) Score for Baseline Press Rate at Week 6 and Week 12 Change from Baseline at Week 6	0.461 score on a scale Standard Deviation 0.844	0.195 score on a scale Standard Deviation 1.181	—	—	—	—	—
Change From Baseline in the Effort Expenditure for Reward Task (EEfRT) Score for Baseline Press Rate at Week 6 and Week 12 Stage 2 Baseline	—	—	3.38 score on a scale Standard Deviation 1.284	3.67 score on a scale Standard Deviation 0.904	—	—	—
Change From Baseline in the Effort Expenditure for Reward Task (EEfRT) Score for Baseline Press Rate at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.109 score on a scale Standard Deviation 0.909	0.354 score on a scale Standard Deviation 1.076	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized test that reliably measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. For each trial, participants are asked to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. EEfRT scores are analyzed for 8 variables. Variable 2 is the choice RT and is defined as the average RT measured in milliseconds for making a choice during the first 50 trials. Scores range from 0 to 10,000. The target range is greater than 500. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=65 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=18 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the EEfRT Score for Choice Reaction Time (RT) 1st 50 at Week 6 and Week 12 Stage 1 Baseline	1339.5 score on a scale Standard Deviation 838.40	1659.4 score on a scale Standard Deviation 1063.02	—	—	—	—	—
Change From Baseline in the EEfRT Score for Choice Reaction Time (RT) 1st 50 at Week 6 and Week 12 Change from Baseline at Week 6	-255.1 score on a scale Standard Deviation 551.65	-346.6 score on a scale Standard Deviation 1108.63	—	—	—	—	—
Change From Baseline in the EEfRT Score for Choice Reaction Time (RT) 1st 50 at Week 6 and Week 12 Stage 2 Baseline	—	—	1309.4 score on a scale Standard Deviation 595.02	1283.5 score on a scale Standard Deviation 875.79	—	—	—
Change From Baseline in the EEfRT Score for Choice Reaction Time (RT) 1st 50 at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-288.8 score on a scale Standard Deviation 527.42	-110.2 score on a scale Standard Deviation 812.66	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized test that reliably measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. For each trial, participants are asked to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. EEfRT scores are analyzed for 8 variables. Variable 3 is the proportion of completed task (easy or hard) during the first 50 trials. Scores range from 0 to 1, with higher scores indicative of better task compliance. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=66 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=18 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the EEfRT Score for Completed Tasks at Week 6 and Week 12 Stage 1 Baseline	0.790 score on a scale Standard Deviation 0.285	0.749 score on a scale Standard Deviation 0.294	—	—	—	—	—
Change From Baseline in the EEfRT Score for Completed Tasks at Week 6 and Week 12 Change from Baseline at Week 6	-0.032 score on a scale Standard Deviation 0.196	0.001 score on a scale Standard Deviation 0.209	—	—	—	—	—
Change From Baseline in the EEfRT Score for Completed Tasks at Week 6 and Week 12 Stage 2 Baseline	—	—	0.703 score on a scale Standard Deviation 0.329	0.779 score on a scale Standard Deviation 0.254	—	—	—
Change From Baseline in the EEfRT Score for Completed Tasks at Week 6 and Week 12 Change from Baseline at Week 12	—	—	0.049 score on a scale Standard Deviation 0.223	-0.022 score on a scale Standard Deviation 0.173	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized test that reliably measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. For each trial, participants are asked to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. EEfRT scores are analyzed for 8 variables. Variable 4 is the proportion of hard task choices made for the low (12%) probability condition during the first 50 trials of the task. Scores range from 0 to 1, with higher scores indicative of greater effort expenditure. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=65 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=17 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the EEfRT Score for 12% Probability-Proportion High Effort Opts at Week 6 and Week 12 Change from Baseline at Week 6	-0.021 score on a scale Standard Deviation 0.064	-0.004 score on a scale Standard Deviation 0.082	—	—	—	—	—
Change From Baseline in the EEfRT Score for 12% Probability-Proportion High Effort Opts at Week 6 and Week 12 Stage 1 Baseline	0.080 score on a scale Standard Deviation 0.071	0.0755 score on a scale Standard Deviation 0.079	—	—	—	—	—
Change From Baseline in the EEfRT Score for 12% Probability-Proportion High Effort Opts at Week 6 and Week 12 Stage 2 Baseline	—	—	0.040 score on a scale Standard Deviation 0.049	0.071 score on a scale Standard Deviation 0.063	—	—	—
Change From Baseline in the EEfRT Score for 12% Probability-Proportion High Effort Opts at Week 6 and Week 12 Change from Baseline at Week 12	—	—	0.000 score on a scale Standard Deviation 0.045	-0.027 score on a scale Standard Deviation 0.051	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized test that reliably measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. For each trial, participants are asked to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. EEfRT scores are analyzed for 8 variables. Variable 5 is the proportion of hard task choices made for the medium (50%) probability condition during the first 50 trials of the task. Scores range from 0 to 1, with higher scores indicative of greater effort expenditure. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=65 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=17 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the EEfRT Score for 50% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 1 Baseline	0.088 score on a scale Standard Deviation 0.070	0.078 score on a scale Standard Deviation 0.081	—	—	—	—	—
Change From Baseline in the EEfRT Score for 50% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 6	-0.026 score on a scale Standard Deviation 0.055	-0.012 score on a scale Standard Deviation 0.102	—	—	—	—	—
Change From Baseline in the EEfRT Score for 50% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 2 Baseline	—	—	0.060 score on a scale Standard Deviation 0.057	0.062 score on a scale Standard Deviation 0.078	—	—	—
Change From Baseline in the EEfRT Score for 50% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.016 score on a scale Standard Deviation 0.068	-0.005 score on a scale Standard Deviation 0.083	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized test that reliably measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. For each trial, participants are asked to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. EEfRT scores are analyzed for 8 variables. Variable 6 is the proportion of hard task choices made for the hard (88%) probability condition during the first 50 trials of the task. Scores range from 0 to 1, with higher scores indicative of greater effort expenditure. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=65 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=17 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the EEfRT Score for 88% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 1 Baseline	0.082 score on a scale Standard Deviation 0.063	0.081 score on a scale Standard Deviation 0.086	—	—	—	—	—
Change From Baseline in the EEfRT Score for 88% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 6	-0.021 score on a scale Standard Deviation 0.072	-0.006 score on a scale Standard Deviation 0.097	—	—	—	—	—
Change From Baseline in the EEfRT Score for 88% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 2 Baseline	—	—	0.052 score on a scale Standard Deviation 0.065	0.078 score on a scale Standard Deviation 0.074	—	—	—
Change From Baseline in the EEfRT Score for 88% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.015 score on a scale Standard Deviation 0.047	-0.015 score on a scale Standard Deviation 0.070	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized test that reliably measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. For each trial, participants are asked to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. EEfRT scores are analyzed for 8 variables. Variable 7 is the overall proportion of hard task choices made for the first 50 trials of the task. Scores range from 0 to 1, with higher scores indicative of greater effort expenditure. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=65 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=17 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the EEfRT Score for All-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 1 Baseline	0.251 score on a scale Standard Deviation 0.185	0.234 score on a scale Standard Deviation 0.234	—	—	—	—	—
Change From Baseline in the EEfRT Score for All-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 6	-0.068 score on a scale Standard Deviation 0.167	-0.022 score on a scale Standard Deviation 0.261	—	—	—	—	—
Change From Baseline in the EEfRT Score for All-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 2 Baseline	—	—	0.152 score on a scale Standard Deviation 0.161	0.210 score on a scale Standard Deviation 0.199	—	—	—
Change From Baseline in the EEfRT Score for All-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.032 score on a scale Standard Deviation 0.144	-0.047 score on a scale Standard Deviation 0.176	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The EEfRT is a multi-trial computerized test that reliably measures drug effects on the willingness to expend effort in relation to the amount of reward or probability of reward. For each trial, participants are asked to choose between 2 tasks that differ in difficulty level and are associated with varying levels of monetary reward. EEfRT scores are analyzed for 8 variables. Variable 8 is the difference between the proportion of hard task choices made for the high probability condition during the first 50 trials of the task. Scores range from -1 to 1, with higher scores indicative of greater sensitivity to probability information. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=42 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=65 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=17 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=25 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the EEfRT Score for Difference - Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 1 Baseline	0.002 score on a scale Standard Deviation 0.041	0.006 score on a scale Standard Deviation 0.037	—	—	—	—	—
Change From Baseline in the EEfRT Score for Difference - Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 6	-0.001 score on a scale Standard Deviation 0.054	-0.002 score on a scale Standard Deviation 0.050	—	—	—	—	—
Change From Baseline in the EEfRT Score for Difference - Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Stage 2 Baseline	—	—	0.012 score on a scale Standard Deviation 0.032	0.006 score on a scale Standard Deviation 0.034	—	—	—
Change From Baseline in the EEfRT Score for Difference - Proportion High Effort Opts 1st 50 at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.015 score on a scale Standard Deviation 0.037	0.012 score on a scale Standard Deviation 0.039	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations

Treatment effect was evaluated by analyzing the proportion of participants with a 20% reduction from Baseline in the PANSS total score with SPCD analysis.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Number of Participants With a Reduction of 20% or Greater in the PANSS Total Score at Week 6 and Week 12 Week 6; Response = Yes	5 Participants	3 Participants	—	—	—	—	—
Number of Participants With a Reduction of 20% or Greater in the PANSS Total Score at Week 6 and Week 12 Week 6; Response = No	42 Participants	77 Participants	—	—	—	—	—
Number of Participants With a Reduction of 20% or Greater in the PANSS Total Score at Week 6 and Week 12 Week 12; Response = Yes	—	—	1 Participants	3 Participants	—	—	—
Number of Participants With a Reduction of 20% or Greater in the PANSS Total Score at Week 6 and Week 12 Week 12; Response = No	—	—	29 Participants	30 Participants	—	—	—

SECONDARY outcome

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

Population: Stage 1 and Stage 2 mITT Populations. Only those participants with available data were analyzed.

The NSA-4 is comprised of the 4 NSA-16 items as follows: 1) restricted speech quantity, 2) emotion: reduced range, 3) reduced social drive, and 4) reduced interests, as well as an overall global rating of negative symptoms. The NSA-16 is a measure of the presence, severity, and range of negative symptoms associated with schizophrenia. It has a high interrater and test-retest reliability across languages and cultures. The possible NSA-4 total score ranges from 4 to 24, with higher scores indicating greater clinical severity of symptoms. Change was Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Stage 1: AVP-786 n=47 Participants Participants were randomized to receive AVP-786 once daily (QD) on Day 1 for the first 7 days. Scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 milligrams twice a day (d6-DM 34 mg/Q 4.9 mg BID). Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1: Placebo n=80 Participants Participants were randomized to receive placebo capsules matched to AVP-786 orally BID. Participants who completed Stage 1 were eligible to participate in Stage 2.	Stage 1 Placebo Non-responders; Stage 2: Placebo n=30 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Non-responders; Stage 2: AVP-786 n=33 Participants Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 Placebo Responders; Stage 2: Placebo Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive placebo capsules matched to AVP-786 orally BID for the entire duration of Stage 2.	Stage 1 Placebo Responders; Stage 2: AVP-786 Participants who were randomized to receive placebo in Stage 1 and were classified as responders were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1: AVP-786 QD on Day 1 for the first 7 days; scheduled dose escalations occurred on Day 8 and Day 14 to a target dose of AVP-786-34/4.9 BID.	Stage 1 AVP-786; Stage 2: AVP-786 Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Change From Baseline in the 4-Item NSA (NSA-4) Total Score at Week 6 and Week 12 Stage 1 Baseline	17.4 score on a scale Standard Deviation 2.44	17.3 score on a scale Standard Deviation 2.36	—	—	—	—	—
Change From Baseline in the 4-Item NSA (NSA-4) Total Score at Week 6 and Week 12 Change from Baseline at Week 6	-1.0 score on a scale Standard Deviation 2.10	-1.0 score on a scale Standard Deviation 1.92	—	—	—	—	—
Change From Baseline in the 4-Item NSA (NSA-4) Total Score at Week 6 and Week 12 Stage 2 Baseline	—	—	16.5 score on a scale Standard Deviation 2.64	16.4 score on a scale Standard Deviation 2.84	—	—	—
Change From Baseline in the 4-Item NSA (NSA-4) Total Score at Week 6 and Week 12 Change from Baseline at Week 12	—	—	-0.5 score on a scale Standard Deviation 2.01	-0.5 score on a scale Standard Deviation 1.93	—	—	—

Adverse Events

All Placebo

Serious events: 2 serious events

Other events: 39 other events

Deaths: 0 deaths

All AVP-786

Serious events: 0 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	All Placebo n=96 participants at risk Participants who received placebo in Stage 1 or Stage 2.	All AVP-786 n=88 participants at risk Participants who received AVP-786 in Stage 1 or Stage 2 (up to a target dose of AVP-786-34/4.9 milligrams twice a day \[d6-DM 34 mg/Q 4.9 mg BID\]).
Infections and infestations Urinary tract infection	1.0% 1/96 • All adverse events (AEs) were collected for approximately 90 days. Treatment-emergent adverse events (TEAEs) are reported and defined as any AE that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of study medication (first dose on or before AE start date which was on or before the date of last dose +30 days). All serious adverse events are reported.	0.00% 0/88 • All adverse events (AEs) were collected for approximately 90 days. Treatment-emergent adverse events (TEAEs) are reported and defined as any AE that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of study medication (first dose on or before AE start date which was on or before the date of last dose +30 days). All serious adverse events are reported.
Psychiatric disorders Schizophrenia	1.0% 1/96 • All adverse events (AEs) were collected for approximately 90 days. Treatment-emergent adverse events (TEAEs) are reported and defined as any AE that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of study medication (first dose on or before AE start date which was on or before the date of last dose +30 days). All serious adverse events are reported.	0.00% 0/88 • All adverse events (AEs) were collected for approximately 90 days. Treatment-emergent adverse events (TEAEs) are reported and defined as any AE that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of study medication (first dose on or before AE start date which was on or before the date of last dose +30 days). All serious adverse events are reported.

Other adverse events

Additional Information

Sanjay Dubé, M.D.

Avanir Pharmaceuticals, Inc.

Phone: 949-389-6700

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place