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

• Sponsor: Avanir Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02477670
• Collaborator: (none)
• Enrollment: 145
• Locations: 17
• Arms: 2
• Actual Duration (Months): 22.6
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The objectives of this 12-week study are to evaluate the efficacy, safety, and tolerability of AVP-786 as an adjunctive treatment compared with placebo in patients with residual schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: AVP-786; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 145 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Sequential Parallel Comparison Design (SPCD) Study to Assess the Efficacy, Safety and Tolerability of AVP-786 (Deuterated [d6]-Dextromethorphan Hydrobromide [d6-DM]/Quinidine Sulfate [Q]) as an Adjunctive Treatment for Patients With Residual Schizophrenia
• Actual Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Jul 21, 2017
• Actual Study Completion Date: Jul 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo capsules administered twice a day over a 12-week period	Drug: Placebo
Experimental: AVP-786 AVP-786 dose 2 capsules administered twice a day over a 12-week period	Drug: AVP-786

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the 16-Item Negative Symptom Assessment (NSA-16) Total Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

Secondary Outcome Measures

1. Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

2. Change From Baseline in the PANSS Negative Subscale Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

3. Change From Baseline in the PANSS Marder Negative Factor Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

4. Change From Baseline in the PANSS Prosocial Factor Subscale Score at Week 6 at Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

5. Change From Baseline in the PANSS Positive Subscale Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

6. Change From Baseline in the PANSS General Psychopathology Subscale Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

7. Change From Baseline in the PANSS Excitement Component Subscale Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

8. Change From Baseline in the NSA-16 Communication Domain Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

9. Change From Baseline in the NSA-16 Emotion/Affect Domain Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

   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.

10. Change From Baseline in the NSA-16 Social Involvement Domain Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

11. Change From Baseline in the NSA-16 Motivation Domain Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

12. Change From Baseline in the NSA-16 Retardation Domain Score at Week 6 at Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

13. Change From Baseline in the NSA-16 Global Negative Symptoms Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

14. Change From Baseline in the NSA-16 Global Level of Functioning Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

15. 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 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

16. Mean Actual Clinical Global Impression of Severity (CGI-S) of Illness Score at Week 6 and Week 12 [Week 6 (Stage 1); Week 12 (Stage 2)]

    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.

17. Mean Actual Clinical Global Impression of Change (CGI-C) Score at Week 6 and Week 12 [Baseline, Week 6 (Stage 1), Week 12 (Stage 2)]

    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.

18. Mean Actual Patient Global Impression of Change (PGI-C) Score at Week 6 at Week 12 [Baseline, Week 6 (Stage 1), Week 12 (Stage 2)]

    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.

19. Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) Total Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

20. Change From Baseline in the Effort Expenditure for Reward Task (EEfRT) Score for Baseline Press Rate at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

21. Change From Baseline in the EEfRT Score for Choice Reaction Time (RT) 1st 50 at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

22. Change From Baseline in the EEfRT Score for Completed Tasks at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

23. Change From Baseline in the EEfRT Score for 12% Probability-Proportion High Effort Opts at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

24. Change From Baseline in the EEfRT Score for 50% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

25. Change From Baseline in the EEfRT Score for 88% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

26. Change From Baseline in the EEfRT Score for All-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

27. Change From Baseline in the EEfRT Score for Difference - Proportion High Effort Opts 1st 50 at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

28. Number of Participants With a Reduction of 20% or Greater in the PANSS Total Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

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

29. Change From Baseline in the 4-Item NSA (NSA-4) Total Score at Week 6 and Week 12 [Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients who meet DSM-IV-TR diagnostic criteria for schizophrenia using the M.I.N.I. version 6.0.

• Patients must meet PANSS criteria

• Patients currently receiving atypical antipsychotics are eligible provided they are on a stable dose

Exclusion Criteria:

• Patients with current major depressive disorder (MDD)

• Patients with extrapyramidal syndrome secondary to their ongoing antipsychotic medication

• Patients currently using anticholinergic medications

• Recent in-patient hospitalization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Cerritos	California	United States
2		Garden Grove	California	United States
3		National City	California	United States
4		Oakland	California	United States
5		San Diego	California	United States
6		Washington	District of Columbia	United States
7		Orlando	Florida	United States
8		Atlanta	Georgia	United States
9		Augusta	Georgia	United States
10		Chicago	Illinois	United States
11		Boston	Massachusetts	United States
12		Worcester	Massachusetts	United States
13		Grand Rapids	Michigan	United States
14		Marlton	New Jersey	United States
15		Jamaica	New York	United States
16		New York	New York	United States
17		Rochester	New York	United States

Sponsors and Collaborators

• Avanir Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 15, 2017
• Study Protocol - Jan 25, 2016

More Information

Publications

None provided.

• Responsible Party: Avanir Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02477670
• Other Study ID Numbers: 15-AVP-786-202
• First Posted: Jun 23, 2015
• Last Update Posted: Sep 16, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Avanir Pharmaceuticals: Negative Symptoms; Schizophrenia; AVP-786
• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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).

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Period Title: Stage 1
STARTED	47	80	0	0	0	0	0
COMPLETED	43	67	0	0	0	0	0
NOT COMPLETED	4	13	0	0	0	0	0
Period Title: Stage 1
STARTED	0	0	30	33	2	1	42
COMPLETED	0	0	28	32	2	1	42
NOT COMPLETED	0	0	2	1	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	AVP-786	Total
Arm/Group Description	Participants were randomized to receive placebo capsules matched to AVP-786 orally twice a day (BID) in Stage 1.	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 of all reporting groups
Overall Participants	96	48	144
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.9 (10.83)	46.5 (12.04)	45.4 (11.23)
Sex: Female, Male (Count of Participants)
Female	27 28.1%	18 37.5%	45 31.3%
Male	69 71.9%	30 62.5%	99 68.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 12.5%	4 8.3%	16 11.1%
Not Hispanic or Latino	84 87.5%	44 91.7%	128 88.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	4 4.2%	4 8.3%	8 5.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	53 55.2%	25 52.1%	78 54.2%
White	36 37.5%	18 37.5%	54 37.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 3.1%	1 2.1%	4 2.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the 16-Item Negative Symptom Assessment (NSA-16) Total Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	61.0 (7.53)	60.4 (7.71)
Change from Baseline at Week 6	-5.0 (5.64)	-3.4 (5.54)
Stage 2 Baseline	57.6 (9.39)	57.6 (9.09)
Change from Baseline at Week 12	-2.4 (5.88)	-3.7 (6.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Sequential Parallel Comparison Design (SPCD) Weighted Ordinary Least Squares (OLS) z-statistic. Treatment differences in each stage were estimated by the Mixed Model Repeated Measures (MMRM).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.79
	Confidence Interval	(2-Sided) 95%; -3.75 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	67.4 (8.26)	68.7 (7.99)
Change from Baseline at Week 6	-4.7 (6.98)	-2.5 (6.50)
Stage 2 Baseline	67.1 (9.00)	65.6 (8.07)
Change from Baseline at Week 12	-1.4 (7.64)	-4.0 (7.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-2.25
	Confidence Interval	(2-Sided) 95%; -4.21 to -0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the PANSS Negative Subscale Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	24.6 (3.51)	25.2 (3.64)
Change from Baseline at Week 6	-2.2 (3.33)	-1.5 (3.81)
Stage 2 Baseline	24.4 (4.55)	23.6 (4.53)
Change from Baseline at Week 12	-1.0 (2.69)	-2.3 (3.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-2.20
	Confidence Interval	(2-Sided) 95%; -4.16 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the PANSS Marder Negative Factor Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	24.1 (4.24)	24.2 (3.81)
Change from Baseline at Week 6	-2.1 (3.34)	-1.6 (3.48)
Stage 2 Baseline	23.0 (4.62)	22.3 (5.45)
Change from Baseline at Week 12	-0.8 (2.80)	-2.5 (4.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-2.26
	Confidence Interval	(2-Sided) 95%; -4.22 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in the PANSS Prosocial Factor Subscale Score at Week 6 at Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	18.3 (3.24)	18.4 (2.92)
Change from Baseline at Week 6	-2.0 (2.18)	-1.1 (2.53)
Stage 2 Baseline	17.7 (3.27)	17.0 (3.30)
Change from Baseline at Week 12	-0.7 (2.02)	-1.4 (2.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-2.60
	Confidence Interval	(2-Sided) 95%; -4.56 to -0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in the PANSS Positive Subscale Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	13.6 (3.65)	13.4 (2.81)
Change from Baseline at Week 6	-0.8 (2.63)	-0.3 (2.57)
Stage 2 Baseline	13.1 (3.64)	13.3 (3.39)
Change from Baseline at Week 12	-0.4 (1.99)	-0.3 (2.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.700
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -2.35 to 1.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in the PANSS General Psychopathology Subscale Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	29.1 (4.66)	30.1 (5.05)
Change from Baseline at Week 6	-1.7 (4.04)	-0.7 (3.21)
Stage 2 Baseline	29.7 (5.40)	28.7 (4.84)
Change from Baseline at Week 12	0.0 (5.14)	-1.3 (5.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.054
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.93
	Confidence Interval	(2-Sided) 95%; -3.89 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the PANSS Excitement Component Subscale Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	6.2 (1.57)	6.3 (2.10)
Change from Baseline at Week 6	-0.4 (1.64)	-0.2 (1.57)
Stage 2 Baseline	5.8 (1.27)	6.7 (2.59)
Change from Baseline at Week 12	0.0 (2.04)	-0.1 (1.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.723
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -2.31 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in the NSA-16 Communication Domain Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	12.5 (2.54)	12.6 (2.71)
Change from Baseline at Week 6	-1.3 (2.32)	-1.0 (1.91)
Stage 2 Baseline	12.0 (2.98)	11.8 (3.12)
Change from Baseline at Week 12	-0.4 (1.86)	-1.0 (1.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.85
	Confidence Interval	(2-Sided) 95%; -3.81 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in the NSA-16 Emotion/Affect Domain Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	12.6 (2.11)	12.2 (1.81)
Change from Baseline at Week 6	-1.0 (1.28)	-0.6 (1.54)
Stage 2 Baseline	11.7 (1.84)	11.7 (2.09)
Change from Baseline at Week 12	-0.4 (1.50)	-0.6 (1.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.64
	Confidence Interval	(2-Sided) 95%; -3.6 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in the NSA-16 Social Involvement Domain Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	12.2 (2.02)	12.2 (2.20)
Change from Baseline at Week 6	-0.6 (1.87)	-0.3 (1.92)
Stage 2 Baseline	12.1 (2.12)	12.0 (2.56)
Change from Baseline at Week 12	-0.8 (1.40)	-1.1 (2.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.388
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.86
	Confidence Interval	(2-Sided) 95%; -2.82 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in the NSA-16 Motivation Domain Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	16.5 (2.37)	16.7 (2.33)
Change from Baseline at Week 6	-1.4 (1.96)	-0.9 (1.80)
Stage 2 Baseline	15.8 (2.61)	15.8 (2.39)
Change from Baseline at Week 12	-0.4 (2.13)	-0.4 (2.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.367
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.90
	Confidence Interval	(2-Sided) 95%; -2.86 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in the NSA-16 Retardation Domain Score at Week 6 at Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	7.2 (1.54)	6.7 (1.61)
Change from Baseline at Week 6	-0.8 (1.46)	-0.6 (1.20)
Stage 2 Baseline	6.0 (2.00)	6.3 (2.05)
Change from Baseline at Week 12	-0.3 (1.20)	-0.5 (1.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.447
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -2.72 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in the NSA-16 Global Negative Symptoms Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	4.6 (0.64)	4.6 (0.61)
Change from Baseline at Week 6	-0.4 (0.68)	-0.2 (0.64)
Stage 2 Baseline	4.3 (0.71)	4.4 (0.75)
Change from Baseline at Week 12	-0.1 (0.51)	-0.5 (0.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-2.23
	Confidence Interval	(2-Sided) 95%; -4.19 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline in the NSA-16 Global Level of Functioning Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	46	80	29	33	0	0	0
Stage 1 Baseline	4.7 (0.73)	4.6 (0.63)
Change from Baseline at Week 6	-0.4 (0.61)	-0.2 (0.55)
Stage 2 Baseline	4.5 (0.74)	4.4 (0.70)
Change from Baseline at Week 12	-0.3 (0.52)	-0.3 (0.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.106
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.62
	Confidence Interval	(2-Sided) 95%; -3.58 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	32.5 (11.37)	28.8 (13.09)
Change from Baseline at Week 6	1.2 (5.11)	1.6 (4.55)
Stage 2 Baseline	31.7 (14.99)	28.9 (10.69)
Change from Baseline at Week 12	-1.6 (4.06)	1.6 (3.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	1.78
	Confidence Interval	(2-Sided) 95%; -0.18 to 3.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Mean Actual Clinical Global Impression of Severity (CGI-S) of Illness Score at Week 6 and Week 12
Description	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.
Time Frame	Week 6 (Stage 1); Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	46	78	30	31	0	0	0
Week 6	3.6 (0.80)	3.8 (0.77)
Week 12	3.7 (0.75)	3.5 (0.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.427
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.79
	Confidence Interval	(2-Sided) 95%; -2.75 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Mean Actual Clinical Global Impression of Change (CGI-C) Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline, Week 6 (Stage 1), Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	78	30	32	0	0	0
Week 6	3.4 (0.80)	3.6 (0.69)
Week 12	3.8 (0.90)	3.5 (0.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0566
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.91
	Confidence Interval	(2-Sided) 95%; -3.87 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Mean Actual Patient Global Impression of Change (PGI-C) Score at Week 6 at Week 12
Description	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.
Time Frame	Baseline, Week 6 (Stage 1), Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	75	30	32	0	0	0
Week 6	3.1 (0.94)	3.2 (1.01)
Week 12	3.3 (0.78)	2.9 (1.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1700
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.37
	Confidence Interval	(2-Sided) 95%; -3.33 to 0.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) Total Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	1.1 (1.34)	0.9 (1.31)
Chane from Baseline at Week 6	-0.2 (1.34)	-0.1 (1.02)
Stage 2 Baseline	1.0 (1.56)	0.8 (1.54)
Change from Baseline at Week 12	-0.4 (1.24)	-0.0 (1.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.595
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; -1.43 to 2.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Change From Baseline in the Effort Expenditure for Reward Task (EEfRT) Score for Baseline Press Rate at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	66	18	25	0	0	0
Stage 1 Baseline	3.39 (1.137)	3.39 (1.112)
Change from Baseline at Week 6	0.461 (0.844)	0.195 (1.181)
Stage 2 Baseline	3.38 (1.284)	3.67 (0.904)
Change from Baseline at Week 12	-0.109 (0.909)	0.354 (1.076)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	2.284
	Confidence Interval	(2-Sided) 95%; 0.324 to 4.244
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Change From Baseline in the EEfRT Score for Choice Reaction Time (RT) 1st 50 at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	65	18	25	0	0	0
Stage 1 Baseline	1339.5 (838.40)	1659.4 (1063.02)
Change from Baseline at Week 6	-255.1 (551.65)	-346.6 (1108.63)
Stage 2 Baseline	1309.4 (595.02)	1283.5 (875.79)
Change from Baseline at Week 12	-288.8 (527.42)	-110.2 (812.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.862
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -2.13 to 1.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in the EEfRT Score for Completed Tasks at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	66	18	25	0	0	0
Stage 1 Baseline	0.790 (0.285)	0.749 (0.294)
Change from Baseline at Week 6	-0.032 (0.196)	0.001 (0.209)
Stage 2 Baseline	0.703 (0.329)	0.779 (0.254)
Change from Baseline at Week 12	0.049 (0.223)	-0.022 (0.173)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.251
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.149
	Confidence Interval	(2-Sided) 95%; -3.109 to 0.811
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change From Baseline in the EEfRT Score for 12% Probability-Proportion High Effort Opts at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	65	17	25	0	0	0
Stage 1 Baseline	0.080 (0.071)	0.0755 (0.079)
Change from Baseline at Week 6	-0.021 (0.064)	-0.004 (0.082)
Stage 2 Baseline	0.040 (0.049)	0.071 (0.063)
Change from Baseline at Week 12	0.000 (0.045)	-0.027 (0.051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.246
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-1.159
	Confidence Interval	(2-Sided) 95%; -3.119 to 0.801
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline in the EEfRT Score for 50% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	65	17	25	0	0	0
Stage 1 Baseline	0.088 (0.070)	0.078 (0.081)
Change from Baseline at Week 6	-0.026 (0.055)	-0.012 (0.102)
Stage 2 Baseline	0.060 (0.057)	0.062 (0.078)
Change from Baseline at Week 12	-0.016 (0.068)	-0.005 (0.083)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.818
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	0.231
	Confidence Interval	(2-Sided) 95%; -1.729 to 2.191
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Change From Baseline in the EEfRT Score for 88% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	65	17	25	0	0	0
Stage 1 Baseline	0.082 (0.063)	0.081 (0.086)
Change from Baseline at Week 6	-0.021 (0.072)	-0.006 (0.097)
Stage 2 Baseline	0.052 (0.065)	0.078 (0.074)
Change from Baseline at Week 12	-0.015 (0.047)	-0.015 (0.070)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.968
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.040
	Confidence Interval	(2-Sided) 95%; -2.00 to 1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Change From Baseline in the EEfRT Score for All-Proportion High Effort Opts 1st 50 at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	65	17	25	0	0	0
Stage 1 Baseline	0.251 (0.185)	0.234 (0.234)
Change from Baseline at Week 6	-0.068 (0.167)	-0.022 (0.261)
Stage 2 Baseline	0.152 (0.161)	0.210 (0.199)
Change from Baseline at Week 12	-0.032 (0.144)	-0.047 (0.176)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.760
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	-0.306
	Confidence Interval	(2-Sided) 95%; -2.266 to 1.654
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Change From Baseline in the EEfRT Score for Difference - Proportion High Effort Opts 1st 50 at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	42	65	17	25	0	0	0
Stage 1 Baseline	0.002 (0.041)	0.006 (0.037)
Change from Baseline at Week 6	-0.001 (0.054)	-0.002 (0.050)
Stage 2 Baseline	0.012 (0.032)	0.006 (0.034)
Change from Baseline at Week 12	-0.015 (0.037)	0.012 (0.039)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.214
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	1.243
	Confidence Interval	(2-Sided) 95%; -0.717 to 3.203
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Number of Participants With a Reduction of 20% or Greater in the PANSS Total Score at Week 6 and Week 12
Description	Treatment effect was evaluated by analyzing the proportion of participants with a 20% reduction from Baseline in the PANSS total score with SPCD analysis.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

Stage 1 and Stage 2 mITT Populations

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Week 6; Response = Yes	5 5.2%	3 6.3%
Week 6; Response = No	42 43.8%	77 160.4%
Week 12; Response = Yes	1 1%	3 6.3%
Week 12; Response = No	29 30.2%	30 62.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments
	Method	SPCD 1 degree of freedom score test
	Comments

30. Secondary Outcome

Title	Change From Baseline in the 4-Item NSA (NSA-4) Total Score at Week 6 and Week 12
Description	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.
Time Frame	Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage 1: AVP-786	Stage 1: Placebo	Stage 1 Placebo Non-responders; Stage 2: Placebo	Stage 1 Placebo Non-responders; Stage 2: AVP-786	Stage 1 Placebo Responders; Stage 2: Placebo	Stage 1 Placebo Responders; Stage 2: AVP-786	Stage 1 AVP-786; Stage 2: AVP-786
Arm/Group Description	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.	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.	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.	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.	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.	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.	Participants who received AVP-786 in Stage 1 continued to receive AVP-786 BID in Stage 2 with no further dose escalations.
Measure Participants	47	80	30	33	0	0	0
Stage 1 Baseline	17.4 (2.44)	17.3 (2.36)
Change from Baseline at Week 6	-1.0 (2.10)	-1.0 (1.92)
Stage 2 Baseline	16.5 (2.64)	16.4 (2.84)
Change from Baseline at Week 12	-0.5 (2.01)	-0.5 (1.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: AVP-786, Stage 1: Placebo, Stage 1 Placebo Non-responders; Stage 2: Placebo, Stage 1 Placebo Non-responders; Stage 2: AVP-786
	Comments	Treatment differences in each stage were estimated by the MMRM.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	-0.06
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	SPCD Weighted OLS z-statistic
	Estimated Value	0.951
	Confidence Interval	(2-Sided) 95%; -1.009 to 2.911
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All adverse events (AEs) were collected for approximately 90 days.
Adverse Event Reporting Description	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.
Arm/Group Title	All Placebo		All AVP-786
Arm/Group Description	Participants who received placebo in Stage 1 or Stage 2.		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]).
All Cause Mortality
	All Placebo		All AVP-786
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/96 (0%)		0/88 (0%)
Serious Adverse Events
	All Placebo		All AVP-786
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/96 (2.1%)		0/88 (0%)
Infections and infestations
Urinary tract infection	1/96 (1%)		0/88 (0%)
Psychiatric disorders
Schizophrenia	1/96 (1%)		0/88 (0%)
Other (Not Including Serious) Adverse Events
	All Placebo		All AVP-786
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/96 (40.6%)		30/88 (34.1%)
Blood and lymphatic system disorders
Anaemia	0/96 (0%)		1/88 (1.1%)
Lymphopenia	1/96 (1%)		0/88 (0%)
Cardiac disorders
Tachycardia	0/96 (0%)		1/88 (1.1%)
Atrial fibrillation	1/96 (1%)		0/88 (0%)
Eye disorders
Vision blurred	0/96 (0%)		2/88 (2.3%)
Eye pain	1/96 (1%)		0/88 (0%)
Gastrointestinal disorders
Dry mouth	1/96 (1%)		4/88 (4.5%)
Diarrhoea	3/96 (3.1%)		2/88 (2.3%)
Glossitis	0/96 (0%)		1/88 (1.1%)
Haemorrhoids	1/96 (1%)		1/88 (1.1%)
Nausea	0/96 (0%)		1/88 (1.1%)
Abdominal pain upper	1/96 (1%)		0/88 (0%)
Dental discomfort	1/96 (1%)		0/88 (0%)
General disorders
Fatigue	2/96 (2.1%)		1/88 (1.1%)
Pyrexia	1/96 (1%)		0/88 (0%)
Immune system disorders
Seasonal allergy	0/96 (0%)		1/88 (1.1%)
Infections and infestations
Nasopharyngitis	4/96 (4.2%)		3/88 (3.4%)
Upper respiratory tract infection	0/96 (0%)		2/88 (2.3%)
Groin infection	0/96 (0%)		1/88 (1.1%)
Pharyngitis streptococcal	1/96 (1%)		1/88 (1.1%)
Bacterial vaginosis	0/96 (0%)		1/88 (1.1%)
Otitis externa	0/96 (0%)		1/88 (1.1%)
Bronchitis	1/96 (1%)		0/88 (0%)
Conjunctivitis	1/96 (1%)		0/88 (0%)
Influenza	1/96 (1%)		0/88 (0%)
Sinusitis	1/96 (1%)		0/88 (0%)
Tooth infection	1/96 (1%)		0/88 (0%)
Injury, poisoning and procedural complications
Muscle strain	0/96 (0%)		1/88 (1.1%)
Overdose	0/96 (0%)		1/88 (1.1%)
Contusion	0/96 (0%)		1/88 (1.1%)
Limb injury	1/96 (1%)		0/88 (0%)
Scratch	1/96 (1%)		0/88 (0%)
Investigations
Blood creatine phosphokinase increased	0/96 (0%)		2/88 (2.3%)
Blood prolactin increased	0/96 (0%)		1/88 (1.1%)
Metabolism and nutrition disorders
Hyperglycaemia	0/96 (0%)		1/88 (1.1%)
Type 2 diabetes mellitus	0/96 (0%)		1/88 (1.1%)
Hyperkalaemia	0/96 (0%)		1/88 (1.1%)
Hypocalcaemia	0/96 (0%)		1/88 (1.1%)
Decreased appetite	1/96 (1%)		0/88 (0%)
Gout	1/96 (1%)		0/88 (0%)
Hypercholesterolaemia	1/96 (1%)		0/88 (0%)
Increased appetite	1/96 (1%)		0/88 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/96 (0%)		1/88 (1.1%)
Back pain	2/96 (2.1%)		0/88 (0%)
Osteoarthritis	1/96 (1%)		0/88 (0%)
Pain in extremity	1/96 (1%)		0/88 (0%)
Nervous system disorders
Dizziness	3/96 (3.1%)		3/88 (3.4%)
Headache	5/96 (5.2%)		2/88 (2.3%)
Paraesthesia	1/96 (1%)		1/88 (1.1%)
Somnolence	3/96 (3.1%)		1/88 (1.1%)
Dysgeusia	1/96 (1%)		0/88 (0%)
Dyskinesia	1/96 (1%)		0/88 (0%)
Sedation	2/96 (2.1%)		0/88 (0%)
Syncope	1/96 (1%)		0/88 (0%)
Psychiatric disorders
Anxiety	0/96 (0%)		1/88 (1.1%)
Insomnia	0/96 (0%)		1/88 (1.1%)
Sleep disorder	0/96 (0%)		1/88 (1.1%)
Depression	1/96 (1%)		0/88 (0%)
Paranoia	1/96 (1%)		0/88 (0%)
Schizophrenia	1/96 (1%)		0/88 (0%)
Renal and urinary disorders
Glycosuria	0/96 (0%)		1/88 (1.1%)
Urine abnormality	0/96 (0%)		1/88 (1.1%)
Haematuria	1/96 (1%)		0/88 (0%)
Pollakiuria	1/96 (1%)		0/88 (0%)
Reproductive system and breast disorders
Erectile dysfunction	1/96 (1%)		0/88 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/96 (2.1%)		1/88 (1.1%)
Nasal congestion	0/96 (0%)		1/88 (1.1%)
Dyspnoea	1/96 (1%)		0/88 (0%)
Skin and subcutaneous tissue disorders
Hidradenitis	0/96 (0%)		1/88 (1.1%)
Rash	2/96 (2.1%)		1/88 (1.1%)
Night sweats	1/96 (1%)		0/88 (0%)
Rash pruritic	1/96 (1%)		0/88 (0%)
Vascular disorders
Hypertension	1/96 (1%)		1/88 (1.1%)
Orthostatic hypotension	1/96 (1%)		0/88 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.