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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: AVP-786
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo capsules administered twice a day over a 12-week period | Drug: Placebo<br> <br> |
| Experimental: AVP-786<br>AVP-786 dose 2 capsules administered twice a day over a 12-week period | Drug: AVP-786<br> <br> |

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the PANSS Negative Subscale Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the PANSS Marder Negative Factor Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the PANSS Prosocial Factor Subscale Score at Week 6 at Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the PANSS Positive Subscale Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the PANSS General Psychopathology Subscale Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the PANSS Excitement Component Subscale Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the NSA-16 Communication Domain Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the NSA-16 Emotion/Affect Domain Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the NSA-16 Social Involvement Domain Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the NSA-16 Motivation Domain Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the NSA-16 Retardation Domain Score at Week 6 at Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the NSA-16 Global Negative Symptoms Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the NSA-16 Global Level of Functioning Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| 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 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Mean Actual Clinical Global Impression of Severity (CGI-S) of Illness Score at Week 6 and Week 12 | 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. | Week 6 (Stage 1); Week 12 (Stage 2) | 
| Mean Actual Clinical Global Impression of Change (CGI-C) Score at Week 6 and Week 12 | 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. | Baseline, Week 6 (Stage 1), Week 12 (Stage 2) | 
| Mean Actual Patient Global Impression of Change (PGI-C) Score at Week 6 at Week 12 | 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. | Baseline, Week 6 (Stage 1), Week 12 (Stage 2) | 
| Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) Total Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the Effort Expenditure for Reward Task (EEfRT) Score for Baseline Press Rate at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the EEfRT Score for Choice Reaction Time (RT) 1st 50 at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the EEfRT Score for Completed Tasks at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the EEfRT Score for 12% Probability-Proportion High Effort Opts at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the EEfRT Score for 50% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the EEfRT Score for 88% Probability-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the EEfRT Score for All-Proportion High Effort Opts 1st 50 at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the EEfRT Score for Difference - Proportion High Effort Opts 1st 50 at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Number of Participants With a Reduction of 20% or Greater in the PANSS Total Score at Week 6 and Week 12 | Treatment effect was evaluated by analyzing the proportion of participants with a 20% reduction from Baseline in the PANSS total score with SPCD analysis. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 
| Change From Baseline in the 4-Item NSA (NSA-4) Total Score at Week 6 and Week 12 | 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. | Baseline and Week 6 (Stage 1); Baseline (Week 6) and Week 12 (Stage 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AVP-786, Negative Symptoms, Schizophrenia