Clinical trial NCT02477670
Conditions: Schizophrenia
Keywords: Negative Symptoms Schizophrenia AVP-786
Sponsor: Avanir Pharmaceuticals
Start date: 2015-09-01; Completion date: 2017-07-21
Enrollment: 145 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: Placebo capsules administered twice a day over a 12-week period arm 2: AVP-786 dose 2 capsules administered twice a day over a 12-week period
Interventions: intervention 1: AVP-786 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 
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CONFIDENTIAL AND PROPRIETARY INFORMATION OF AVANIR PHARMACEUTICALS, INC. 
Protocol 15-AVP-786-202 
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15-AVP-786-202-Amendment 04 
Version 5.0 
Protocol Amendment 4 (Version 5.0) 
Summary of Changes 
Section 
Number 
Section Title 
Description 
Title Page 
Title page 
The date, version number, and amendment number were 
changed to reflect date of finalization, Version 5.0, 
Amendment 4. 
Study Synopsis 
3.1, and 5.3.1 
Study Design/ 
Randomization and 
Treatment 
Clarified language on the structure of the study, 
randomization and treatment assignment  
4.1 
Inclusion Criteria 
Added inclusion criterion 9 to specify that patients must have 
a reliable informant as deemed appropriate by the 
investigator.  
4.2 
Exclusion Criteria 
 
 
4.3 
Patient Withdrawal 
Revised to:  patients with a QTcF change from ‘pre-dose 
Baseline’ (instead of Screening) ECG of > 60 msec at any 
time after Baseline are to be withdrawn from the study 
5.1.6 
Study Medication 
Administration 
Clarified language on study medication administration 
5.5 
 
 
 
6.3 
 
 
 
 
 
 
6.4.5 
Clinical Laboratory 
Tests 
Added HbA1c at Screening and Visit 7 
Table 2 
PK Blood Sampling 
Footer 
 
Overall 
Minor formatting and administrative updates 


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Protocol Amendment 3 (Version 4.0) 
Summary of Changes 
Section 
Number 
Section Title 
Description 
Title Page 
Title page 
The date, version number, and amendment number were 
changed to reflect date of finalization, Version 4.0, 
Amendment 3. 
4.1 
Inclusion Criteria 
Updated inclusion criteria #4a based on recommendation 
from the IRB to: If female of childbearing potential, patients 
must have a negative urine pregnancy test “(all females 
regardless of childbearing potential will be required to 
submit a pregnancy test)”. 
6.4.4 
Pregnancy Tests 
Updated language as follows:  Urine pregnancy tests (beta-
hCG) will be performed on “all females regardless of 
childbearing potential” at Baseline/Visit 1 (Day 1), Visit 3 
(Day 22), Visit 4 (Day 43), Visit 6 (Day 64), and Visit 
7/Early Termination Visit (Day 85). At the Screening Visit, 
serum beta-hCG will be collected 
Table 2 
Footer 
Updated footer on Table 2 to reflect all females will require 
pregnancy test regardless of childbearing potential. 
6.5.1.1 
Screening Visit 
Updated language to reflect all females will require 
pregnancy test regardless of childbearing potential. 
6.5.1.2 
Visit 1 (Baseline Visit, 
Day 1) 
Updated language to reflect all females will require 
pregnancy test regardless of childbearing potential. 
6.5.1.5 
Visit 3 (Day 22 + 3-day 
window), Week 3 
Updated language to reflect all females will require 
pregnancy test regardless of childbearing potential. 
6.5.1.6 
Visit 4 (Day 43 ± 3-day 
window), Week 6 
Updated language to reflect all females will require 
pregnancy test regardless of childbearing potential. 
6.5.1.9 
Visit 6 (Day 64 + 3-day 
window); Week 9 
Updated language to reflect all females will require 
pregnancy test regardless of childbearing potential. 
6.5.1.10 
Visit 7/Early 
Termination (Day 85 ± 
3-day window), Week 
12 
Updated language to reflect all females will require 
pregnancy test regardless of childbearing potential. 
Overall 
Minor formatting and administrative updates 


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Version 5.0 
Protocol Amendment 2 (Version 3.0) 
Summary of Changes 
Section 
Number 
Section Title 
Description 
Title Page 
Title page 
The date, version number, and amendment number were 
changed to reflect date of finalization, Version 3.0, 
Amendment 2. 
4.1 
Inclusion Criteria 
Added clarity to inclusion #2 regarding residual 
schizophrenia.  Added “and who meet DSM-IV-TR 
diagnostic criteria for residual schizophrenia.” 
4.1 
Inclusion Criteria 
Updated inclusion criteria #4 based on recommendation from 
the IRB to “A female is considered of childbearing potential 
unless she is post-menopausal (i.e., history compatible with 
menopause [i.e., reported lack of menses for ≥ 12 months] 
and no other biological/surgical cause)”.   
4.2 
Exclusion Criteria 
 
 
 
4.2 
Exclusion Criteria 
 
 
 
6.4 
 
 
6.4.6 
Electrocardiograms 
Added triplicate ECGs to be performed at the Screening Visit 
instead of single resting ECG. 
8.5 
 
 
 
Overall 
Minor formatting and administrative updates 


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Version 5.0 
Protocol Amendment 1 (Version 2.0) 
Summary of Changes 
Section 
Number 
Section Title 
Description 
Title Page 
Title page 
The date, version number, and amendment number were 
changed to reflect date of finalization, Version 2.0, 
Amendment 1. 
4.1 
Inclusion Criteria 
Added timeframe to inclusion #1 
 
4.1 
Inclusion Criteria 
 
 
 
 
 
 
 
 
 
 
  
4.1 
Inclusion Criteria 
Added risperidone to the list of allowed atypical 
antipsychotics  
4.2 
Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
4.2 
Exclusion Criteria 
 
6.1.7 
Study Assessments and 
Procedures; Efficacy  


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Section 
Number 
Section Title 
Description 
6.5.3 
Vital Signs, Weight, 
and Height 
Added Visit 2 (Day 15) and Visit 5 (Day 57).  Was missing 
from this section but included already on the Schedule of 
evaluations and procedures table. 
Overall 
Formatting and minor administrative updates to provide 
consistency throughout the document 


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Table of Contents 
List of Tables ............................................................................................................................ 10 
List of Figures .......................................................................................................................... 10 
List of Abbreviations ............................................................................................................... 11 
Protocol Agreement ................................................................................................................. 14 
Study Synopsis ......................................................................................................................... 15 
1 
Introduction ................................................................................................................... 21 
.......................... 22 
.......................... 23 
.......................... 24 
......................... 24 
2 
Objectives ...................................................................................................................... 25 
3 
Study Design and Rationale ......................................................................................... 26 
3.1 
Study Design ................................................................................................................... 26 
3.1.1 
Screening................................................................................................................. 26 
3.1.2 
Stage 1 ..................................................................................................................... 27 
3.1.3 
Stage 2 ..................................................................................................................... 27 
3.2 
Visits ............................................................................................................................... 29 
4 
Study Population ........................................................................................................... 30 
4.1 
Inclusion Criteria ............................................................................................................ 30 
4.2 
Exclusion Criteria ........................................................................................................... 32 
4.3 
Patient Withdrawal ......................................................................................................... 34 
5 
Study Treatments .......................................................................................................... 35 
5.1 
Treatments Administered ................................................................................................ 35 
5.1.1 
Description of Study Medications .......................................................................... 35 
5.1.2 
Composition of Study Medications ........................................................................ 35 
5.1.3 
Packaging ................................................................................................................ 36 
5.1.4 
Labeling .................................................................................................................. 36 
5.1.5 
Storage of Clinical Supplies.................................................................................... 36 
5.1.6 
Study Medication Administration ........................................................................... 37 


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5.2 
Accountability of Study Supplies ................................................................................... 38 
5.2.1 
Receipt of Supplies ................................................................................................. 38 
5.2.2 
Record of Dispensing .............................................................................................. 38 
5.2.3 
Unused Supplies...................................................................................................... 38 
5.3 
Methods of Assigning Patients to Treatment Groups ..................................................... 38 
5.3.1 
Randomization ........................................................................................................ 38 
5.3.2 
Blinding/Masking ................................................................................................... 39 
5.4 
Patient Compliance ......................................................................................................... 40 
.............................................................. 40 
.............................................................. 40 
.............................................................. 40 
6 
Study Assessments and Procedures ............................................................................. 41 
6.1 
Efficacy ........................................................................................................................... 41 
6.1.1 
16-Item Negative Symptom Assessment (NSA-16) ............................................... 41 
6.1.2 
Positive and Negative Syndrome Scale (PANSS) .................................................. 41 
6.1.3 
Clinical Global Impression (CGI) Scales ............................................................... 42 
6.1.4 
Calgary Depression Scale for Schizophrenia (CDSS) ............................................ 43 
6.1.5 
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) ..................... 44 
6.1.6 
Effort Expenditure for Reward Task (EEfRT)........................................................ 44 
......................................................... 44 
6.2 
Pharmacokinetics (PK) ................................................................................................... 45 
........................................................... 45 
........................................................... 45 
........................................................... 45 
6.4 
Safety .............................................................................................................................. 45 
6.4.1 
Adverse Events ....................................................................................................... 45 
6.4.2 
Physical and Neurological Examinations ............................................................... 49 
6.4.3 
Vital Signs, Weight, and Height ............................................................................. 49 
6.4.4 
Pregnancy Tests ...................................................................................................... 50 
6.4.5 
Clinical Laboratory Tests ........................................................................................ 50 
6.4.6 
Electrocardiograms ................................................................................................. 51 


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6.4.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................... 51 
6.4.8 
Simpson Angus Scale for Extrapyramidal Symptoms (SAS) ................................. 51 
6.4.9 
Barnes Akathisia Scale (BAS) ................................................................................ 52 
6.4.10 Abnormal Involuntary Movements Scale (AIMS) ................................................. 52 
6.5 
Schedule of Evaluations and Procedures ........................................................................ 52 
6.5.1 
Description of Study Procedures ............................................................................ 54 
7 
Data Management ......................................................................................................... 64 
8 
Statistical Methods ........................................................................................................ 65 
8.1 
Analysis Populations ....................................................................................................... 65 
8.2 
Demographic and Baseline Characteristics .................................................................... 65 
8.3 
Efficacy Analysis ............................................................................................................ 65 
8.3.1 
Study Endpoints ...................................................................................................... 65 
8.3.2 
Primary Efficacy Analysis ...................................................................................... 66 
8.3.3 
Secondary Efficacy Analyses ................................................................................. 66 
................................................................................................ 66 
8.5 
Plasma Antipsychotic Levels .......................................................................................... 66 
8.6 
Safety and Tolerability Analysis ..................................................................................... 67 
8.6.1 
Adverse Events ....................................................................................................... 67 
8.6.2 
Vital Signs and ECGs ............................................................................................. 67 
8.6.3 
Clinical Laboratory Values ..................................................................................... 67 
8.6.4 
Data and Safety Monitoring Board ......................................................................... 67 
8.6.5 
Interim Analysis ...................................................................................................... 67 
8.7 
Sample Size Justification ................................................................................................ 67 
9 
Administrative Procedures .......................................................................................... 69 
9.1 
Institutional Review Board Approval ............................................................................. 69 
9.2 
Informed Consent Form .................................................................................................. 69 
9.3 
Quality Assurance ........................................................................................................... 69 
9.3.1 
Documentation ........................................................................................................ 69 
9.3.2 
Monitoring .............................................................................................................. 69 
9.3.3 
Medical Monitoring ................................................................................................ 70 
9.4 
Electronic Case Report Forms ........................................................................................ 70 
9.5 
Record Retention ............................................................................................................ 71 


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9.6 
Source Data ..................................................................................................................... 71 
9.7 
Data Handling ................................................................................................................. 71 
9.8 
Laboratory Procedures .................................................................................................... 71 
9.9 
Guidelines for Good Clinical Practice ............................................................................ 71 
9.10 Conditions for Amending the Protocol ........................................................................... 72 
9.11 Conditions for Terminating the Study ............................................................................ 72 
9.12 Confidentiality of Study Documents and Patient Records ............................................. 72 
9.13 Reports ............................................................................................................................ 72 
9.14 Publications ..................................................................................................................... 72 
9.15 Audits/Inspections .......................................................................................................... 73 
10 
References ...................................................................................................................... 74 
11 
Appendices ..................................................................................................................... 78 
LIST OF TABLES 
Table 1 
Composition of Investigational Products ......................................................36 
Table 2 
Study Schedule of Evaluations and Procedures ...........................................53 
LIST OF FIGURES 
Figure 1 
STUDY SCHEMATIC ....................................................................................28 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AA 
Apathy avolition 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movements Scale  
ALT/SGPT 
Alanine aminotransferase/serum glutamic-pyruvic transaminase 
AST/SGOT 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
AVP-786 
Deuterated [d6]-dextromethorphan hydrobromide and quinidine sulfate 
combination 
BAS 
Barnes Akathisia Scale 
BID 
Twice-daily 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CaMK 
Calmodulin dependent kinase phosphatase 
CDSS 
Calgary Depression Scale for Schizophrenia 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity of Illness  
CK 
Creatine kinase 
CNS 
Central nervous system 
CRO 
Contract research organization 
 
 Subject Database 
d6-DM 
Deuterated (d6)-dextromethorphan hydrobromide 
DBS 
Deep Brain Stimulation 
DE 
Expressive deficits 
DM 
Dextromethorphan hydrobromide 
DMP 
Data Management Plan 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ECT 
Electroconvulsive treatment 
EDC 
Electronic data capture 
EEfRT 
Effort Expenditure for Reward Task 
FDA 
US Food and Drug Administration 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMP 
Good Manufacturing Practice 


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Abbreviation 
Definition 
HBA1c 
Glycosylated hemoglobin 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IP 
Investigational product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IRT 
Interactive Response Technologies 
LDH 
Lactate dehydrogenase 
MAOI 
Monoamine oxidase inhibitor 
MATRICS 
Measurement and Treatment Research to Improve Cognition in Schizophrenia 
MCCB 
MATRICS Consensus Cognitive Battery  
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
M.I.N.I. 
Mini International Neuropsychiatric Interview 
mITT 
Modified Intent-to-Treat 
MM 
Medical Monitor 
MMRM 
Mixed-effects model for repeated measures 
NF 
National Formulary 
NIMH 
National Institute of Mental Health 
NMDA 
N-methyl-D-aspartate 
NSA-16 
16-Item Negative Symptom Assessment 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PBA 
Pseudobulbar affect 
PCP 
Phencyclidine 
PD 
Pharmacodynamic(s) 
pH 
Potential hydrogen 
PK 
Pharmacokinetic(s) 
Q 
Quinidine (sulfate) 
QD 
Once daily 
QOL 
Quality of life 
QRS 
The Q-R-S complex from an ECG tracing 
QT 
QT interval from an ECG tracing 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using the Fridericia’s formula 
RBC 
Red blood cell 
rTMS 
Repetitive Transcranial Magnetic Stimulation 
SAE 
Serious adverse event 


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Abbreviation 
Definition 
SAP 
Statistical analysis plan 
SAS 
Simpson Angus Scale for Extrapyramidal Symptoms 
SDV 
Source of data verification 
SGA 
Second generation antipsychotic 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
SOC 
System Organ Class 
SSRI 
Selective serotonin reuptake inhibitor 
SPCD 
Sequential parallel comparison design 
TEAE 
Treatment-emergent adverse event 
TNFα 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
US 
United States of America 
USP 
United States Pharmacopoeia 
WBC 
White blood cell 
WHO 
World Health Organization 


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PROTOCOL AGREEMENT 
Protocol 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. 
Protocol Number: 15-AVP-786-202 
This document is a confidential communication of Avanir Pharmaceuticals. The recipient agrees that no 
unpublished information contained within this document or protocol will be disclosed or published without 
prior consent and written approval from Avanir. An exception to this agreement may be made for the 
purposes of ethical or regulatory review, in which case this document may be disclosed to an Ethics Review 
Board or any authorized representative of a national authority as required by regulation. 
The signatures of the Principal Investigator and representative of the Sponsor below constitute their 
approval of this protocol and further provide the necessary assurances that: 
1.
This study will be conducted according to Good Clinical Practice (GCP) and to all stipulations, as
specified in both clinical and administrative sections of the protocol including the Declaration of
Helsinki.
2.
The conduct and results of this study will be kept confidential, and the electronic case report forms
(eCRFs) and other pertinent data will become the property of Avanir Pharmaceuticals.
3.
The protocol contains all necessary information required to conduct the study, as outlined in the
protocol, and that the study will not be initiated without the approval of an appropriate Institutional
Review Board (IRB).
4.
All participants in this study will provide written informed consent in accordance with the
requirements specified in the Code of Federal Regulations (21 CFR Parts 50, 56, 312) and/or the
Declaration of Helsinki. All participants will also be informed that their medical records will be kept
confidential except for review by Avanir or its representatives, the U.S. Food and Drug Administration
(FDA), or other regulatory agencies if applicable.
Principal Investigator Signature 
Date 
Principal Investigator Name: 
Avanir Representative Signature 
Date 
Avanir Representative Name: 
 
 


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STUDY SYNOPSIS 
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. 
Study Objectives 
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 on negative and positive symptoms and cognitive function.   
Study Population 
It is estimated that up to 120 patients will participate in the study at approximately 
15 enrolling centers in the US. 
Eligible patients for this study will be adult outpatients (between 18 and 60 years of age) who are 
diagnosed with schizophrenia, are clinically stable, in a residual (non-acute) phase of illness, and 
meet all inclusion and none of the exclusion criteria. Patients enrolled in the study will have been 
treated with a second generation antipsychotic (SGA) agent for at least 3 months (90 days) and on 
a stable dose for 1 month (30 days) prior to the Screening Visit and maintain the same dose 
throughout the course of the study (includes no change from Screening to Baseline/Visit 1 [Day1]). 
Approximately 160 patients will need to be screened (assuming a 25% screen failure rate) in order 
to randomize approximately 120 patients.  
The diagnosis of residual schizophrenia will be based on the Diagnostic and Statistical Manual of 
Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria for schizophrenia, residual 
type.  
An initial diagnostic assessment will be performed by the Investigator to assess if the patient meets 
diagnostic criteria for schizophrenia residual type according to the DSM-IV-TR using the Mini 
International Neuropsychiatric Interview (M.I.N.I.) version 6.0 (Appendix 3), all medical records, 
interviews by clinicians, and when appropriate, interviews with family or other informants. The 
diagnosis will be confirmed by the Investigator.  
 
 
 
 
 
 
  


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Eligible patients are to have otherwise acceptable and stable general health as required by the study 
protocol, and documented by medical history, physical examination, electrocardiogram (ECG), 
and clinical laboratory examinations.   
Eligible patients must be willing to comply with all required study procedures, attend all study 
visits and take the study medication as instructed.    
Participants must provide a signed Informed Consent Form for the procedures in this study 
protocol prior to Screening. 
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, SPCD study to assess 
the efficacy, safety, and tolerability of AVP-786 (deuterated [d6]-dextromethorphan 
hydrobromide [d6-DM]/quinidine sulfate [Q]) of 12 weeks duration as an adjunctive treatment in 
patients with residual schizophrenia. The study consists of an up to 4-week Screening period, a 
12-week double-blind treatment period with 2 consecutive 6-week stages (Stage 1 and Stage 2), 
and a 5-day follow-up by telephone, as shown below. Daily telephone calls will be made for 5 days 
post the Study Exit Visit to assess any changes in health (i.e., adverse events [AEs]) and 
medications (i.e., concomitant medications). 
Sequence 
Screening 
Treatment Period 
Telephone Follow-up 
Stage 1 
Stage 2 
Duration 
Day -28 to -7 
(4 weeks) 
Days 1 to 42 
(6 weeks) 
Days 43 to 85 
(6 weeks) 
Days 86-90 
Screening 
Screening procedures must occur within approximately 4 weeks prior to randomization. The 
Medical Monitor (MM) or contract research organization (CRO) designee will review screening 
procedures for assessment of inclusion and exclusion criteria and consult with the Investigators as 
needed.  
 and Subject Database Authorization 
To reduce duplicate patient enrollment (e.g., enrollment in more than one study 
contemporaneously or in close succession), this study will survey the 
 Subject 
Database 
, a clinical trial registry, for a potential patient match before 
randomization. Patients who match in the 
 with a patient who has participated in 
another clinical trial within the last 30 days will be excluded. 


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Randomization and Treatment 
Stage 1 
Eligible patients will be randomized in a 
 (active:placebo) ratio to receive either AVP-786 or 
matching placebo capsules. Study medication (active or placebo) will be administered orally twice 
daily (BID; 1 capsule in the morning and 1 capsule in the evening, approximately 12 hours apart) 
throughout Stage 1. Patients will be assigned to double-blind treatment for 6 weeks during Stage 
1 as follows: 
•
Patients randomized to AVP-786 at Baseline/Visit 1 (Day 1) will receive AVP-786-
(d6-DM 
 mg/Q 
 mg) once daily (QD) in the morning and placebo in the evening for
the first 7 days. Starting on Day 8, AVP-786-
 will be given BID for the next 7 days
until Day 14. Starting on Day 14, AVP-786 will be dose-escalated up to AVP-786-34/4.9
BID (d6-DM 34 mg/Q 4.9 mg) until the end of Stage 1 (Visit 4 [Day 43]).
•
Patients randomized to placebo will receive placebo BID during the entire Stage 1
(Baseline/Visit 1 [Day 1] to Visit 4 [Day 43]).
All study medication including AVP-786-
 and AVP-786-34/4.9 capsules and placebo 
capsules are of identical appearance in order to maintain the integrity of the blind, including during 
dose-escalation.  
Stage 2 
Patients who complete Stage 1 will be eligible to participate in Stage 2. Study medication will be 
administered orally BID (1 capsule in the morning and 1 capsule in the evening, approximately 12 
hours apart) throughout Stage 2. Patients will be assigned to double-blind treatment for an 
additional 6 weeks during Stage 2 as follows: 
•
Patients who received AVP-786 in Stage 1 will continue to receive AVP-786 BID for the
entire 6-week duration of Stage 2 (Visit 4 to Visit 7/Early Termination Visit [Day 85]) at
the same dose received at the end of Stage 1.
•
Patients who received placebo in Stage 1 will be further stratified into 2 subgroups
(“responders” and “non-responders”) on Visit 4 (Day 43) or Stage 1 Early Termination
Visit based on their treatment response. Patients will be considered “responders” if their
percent of change in 
 from Baseline. Patients who do
not meet this criterion will be considered “non-responders”..
Each placebo subgroup (“responders” and “non-responders”) will then be re-randomized
to receive either AVP-786 or matching placebo in a 
 ratio within each group as follows:


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•
Patients who are re-randomized to placebo will continue to receive placebo BID for the
entire 6-week duration of Stage 2 (Visit 4 up to Visit 7/Early Termination Visit 
[Day 85]). 
•
Patients who are re-randomized to AVP-786 will receive AVP-786 in Stage 2 using the
same dose escalation schedule used in Stage 1.
Assessments and Visits 
Patients will attend a Screening Visit up to 4 weeks prior to the Baseline Visit to determine 
eligibility for the study. During the study, patients will attend clinic visits at Baseline/Visit 1 (Day 
1), Week 2/Visit 2 (Day 15), Week 3/Visit 3 (Day 22), Week 6/Visit 4 (Day 43), Week 8/Visit 5 
(Day 57), Week 9/Visit 6 (Day 64), and Week 12/Visit 7/Early Termination Visit (Day 85). 
Patients will receive telephone follow-up calls at Day 8 and Day 50 to inquire about AEs, 
concomitant medications and study drug compliance, as well as on Days 86 through 90 to inquire 
about AEs and concomitant medications post study treatment. 
The duration of each patient’s participation in this study will be approximately 12 weeks 
(maximum of 17 weeks including Screening period and post study exit telephone calls for 5 days). 
Efficacy Measures 
Primary Efficacy Measure 
The primary efficacy measure is the 16-Item Negative Symptom Assessment (NSA-16) total score. 
Secondary Efficacy Measures 
Secondary efficacy measures to further characterize the effects of AVP-786 on commonly 
associated features of residual schizophrenia include:  
•
PANSS total score, PANSS subscales (positive, negative, general psychopathology,
Marder negative factors, excitement component, and pro-social factors)
•
NSA-16 factor domains, global score, individual items and NSA 4 factors comprised of
the 4 NSA-16 items as follows: 1) restricted speech quantity, 2) reduced emotion,
3) reduced social drive, and 4) reduced interests, as well as an overall global rating of
negative symptoms
•
Proportion of patients with a reduction of 20% or greater in the PANSS total score
•
Measurement and Treatment Research to Improve Cognition in Schizophrenia
(MATRICS) Consensus Cognitive Battery (MCCB) composite score
•
Clinical Global Impression of Severity of Illness (CGI-S), Clinical Global Impression of
Change (CGI-C) and Patient Global Impression of Change (PGIC) scores
•
Calgary Depression Scale for Schizophrenia (CDSS) score


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•
Reward responsiveness using the frequency of hard task choices with moderate probability
reward measured by the probabilistic computerized Effort Expenditure for Reward Task 
(EEfRT) 
•
Pharmacokinetic (PK) Measures 
At Baseline/Visit 1 (Day 1, post-dose), Visit 4 (Day 43) and Visit 7/Early Termination Visit 
(Day 85), all patients will have plasma samples collected between 2 to 3 hours after the morning 
dose of study medication for analysis of study medication (d6-DM, its metabolites, and Q 
concentration levels) and plasma antipsychotic levels. 
 
 
 
 
Safety Measures 
Standard safety will be assessed by reported AEs, serious AEs (SAEs), physical examinations 
(Screening Visit only), vital signs, weight, pregnancy tests, clinical laboratory assessments, and 
resting 12-lead ECGs. In addition, the following scales will be used to assess safety: 
•
Columbia Suicide Severity Rating Scale (C-SSRS)
•
Abnormal Involuntary Movements Scale (AIMS)
•
Barnes Akathisia Scale (BAS)
•
Simpson Angus Scale for Extrapyramidal Symptoms (SAS)
Efficacy Analyses 
Primary Efficacy Analysis 
The primary efficacy analysis is the change from Baseline/Visit 1 (Day 1) to Week 6/Visit 4 (Day 
43, Stage 1) and from Week 6/Visit 4 (Day 43) to Week 12/Visit 7/Early Termination Visit 
(Day 85, Stage 2) of the NSA-16 total score in patients administered AVP-786 compared to 
patients administered placebo, using the SPCD methodology. A weighted ordinary least square 
test statistics combining treatment effects from Stage 1 and 2 will be used. The treatment effect in 
each stage will be analyzed by using a linear mixed-effects model for repeated measures (MMRM). 
Data from Stage 1 placebo non-responders who are re-randomized into Stage 2 will be used to 
estimate the Stage 2 treatment effect.  


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Secondary Efficacy Analyses 
Secondary efficacy endpoints include: change from Baseline/Visit 1 (Day 1) to Week 6/Visit 4 
(Day 43, Stage 1) and from Week 6/Visit 4 (Day 43) to Week 12/Visit 7 (Day 85, Stage 2) for the 
following efficacy measures: PANSS total score; PANSS subscales (positive, negative, general 
psychopathology, Marder negative factors, excitement component, and prosocial factors; NSA-16 
(factor domains, global score, individual items, and NSA 4 factors); proportion of patients with a 
20% reduction in PANSS total score; MCCB composite score; CGI-S, CGI-C, and PGIC scores 
(measure change at post Baseline visits); CDSS; and EEfRT. These endpoints will be analyzed in 
a similar manner as the primary efficacy analysis. 
Pharmacokinetic and Pharmacodynamic (PD) Analysis 
Plasma concentrations of d6-DM, its metabolites, and Q will be measured and results will be 
summarized descriptively overall 
 
 Plasma antipsychotic levels will also be measured and results reported descriptively. 
Plasma concentration results will be used to assess the PK properties of d6-DM, its metabolites, 
and Q as well as potential drug interactions with co-administered antipsychotics. Additional 
PK/PD correlations may also be performed. Additional details will be described in the SAP. 
Sample Size Justification 
Based on published studies such as Kane et al. (1988)1 and Buchanan, et al (2014),2 sample size 
calculations were performed assuming a bivariate normal distribution for the primary endpoint. 


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1 INTRODUCTION 


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2 Objectives  
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 
on negative and positive symptoms and cognitive function. 


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3 Study Design and Rationale 
3.1 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, SPCD study of 12 weeks 
duration, consisting of an up to 4-week Screening period, a 12-week double-blind treatment period 
with 2 consecutive stages (Stage 1 and Stage 2), and a 5-day follow-up by telephone, as shown 
below. Post study exit follow-up telephone calls will be made for 5 days to assess any changes in 
health (i.e., adverse events [AEs]) and medications (i.e., concomitant medications).  
Sequence 
Screening 
Treatment Period 
Telephone Follow-up 
Stage 1 
Stage 2 
Duration 
Days -28 to -7 
(4 weeks) 
Days 1 to 42 
(6 weeks) 
Days 43 to 85 
(6 weeks) 
Days 86-90 
3.1.1 
Screening 
Screening procedures must occur within approximately 4 weeks (28 days) prior to randomization. 
The Medical Monitor (MM) or contract research organization (CRO) designee may review 
Screening procedures for assessment of inclusion and exclusion criteria in consultation with the 
Investigators.  
3.1.1.1 
 and Subject Database Authorization 
Clinical trial registries, such as the 
 Subject Database 
, seek to 
reduce duplicate enrollment by identifying duplicates before randomization.2 At the time of 
providing the Informed Consent Form (ICF) for the study, the Investigator or designee 
will explain the Institutional Review Board (IRB)-approved subject database authorization 
form to the patient and witness the signature. 
During Screening, site staff that have received training, login information, and access to 
 will enter the patient study identification (ID) and authorized patient 
identifiers. An immediate report detailing matches will be generated and should be printed for 
source documentation. The report will specify either (1) no matches found, (2) a match was found 
with a patient participating in another study within 30 days or (3) the patient matches with a patient 
who has pre-screened at another site. 
At the last patient contact, site staff will access 
 again, enter the patient study ID and 
the nature of the last contact (i.e., early termination or completer). 


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3.1.2 
Stage 1 
The Baseline/Visit 1 (Day 1) marks the start of Stage 1 of the study. 
Eligible patients will be randomized at Baseline/Visit 1 (Day 1) in a 
 (active:placebo) ratio to 
receive either AVP-786 capsules or matching placebo capsules. Study medication will be 
administered orally BID (1 capsule in the morning and 1 capsule in the evening, approximately 12 
hours apart) throughout Stage 1. Patients will be assigned to double-blind treatment for 6 weeks 
during Stage 1 as follows: 
•
Patients randomized to AVP-786 at Baseline/Visit 1 (Day 1) will receive AVP-786-
(d6-DM 
 mg/Q 
 mg) once daily (QD) in the morning and placebo in the evening for
the first 7 days. Starting on Day 8, AVP-786-
 will be given BID for the next 7 days
until Day 14. Starting on Day 14, AVP-786 will be dose-escalated up to AVP-786-34/4.9
BID (d6-DM 34 mg/Q 4.9 mg) until the end of Stage 1 (Visit 4 [Day 43]).
•
Patients randomized to placebo will receive placebo BID during the entire Stage 1
(Baseline/Visit 1 [Day 1] to Visit 4 [Day 43]).
All study medication including AVP-786-
 and AVP-786-34/4.9 capsules and matching 
placebo capsules are of identical appearance 
 in order to maintain 
the integrity of the blind, including during dose-escalation. 
3.1.3 
Stage 2 
Patients who complete Stage 1 will be eligible to participate in Stage 2 of the study. Study 
medication will be administered orally BID (1 capsule in the morning and 1 capsule in the evening, 
approximately 12 hours apart) throughout Stage 2. Patients will be assigned to double-blind 
treatment for an additional 6 weeks during Stage 2 as follows. 
•
Patients who received AVP-786 in Stage 1 (Baseline/Visit 1 [Day 1] to Visit 4 [Day 43]),
will continue to receive AVP-786 BID for the entire 6-week duration of Stage 2 (Visit 4 to
Visit 7/Early Termination Visit [Day 85]) at the same dose as at the end of Stage 1.
•
Patients who received placebo in Stage 1 will be further stratified into 2 subgroups
(“responders” and “non-responders”) on Visit 4 (Day 43) or Stage 1 Early Termination
Visit based on their treatment response. Patients will be considered “responders” if their
percent of change in 
 from Baseline.  Patients who do
not meet this criteria will be considered “non-responders”.
Each placebo subgroup (“responders” and “non-responders”) will then be re-randomized
to receive either AVP-786 or matching placebo in a 
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•
Patients who are re-randomized to placebo will continue to receive placebo BID for the
entire 6-week duration of Stage 2 (Visit 4 to Visit 7/Early Termination Visit [Day 85]). 
•
Patients who are re-randomized to AVP-786 will receive AVP-786 in Stage 2 using the
same dose escalation schedule used in Stage 1.
A schematic of the study is shown in Figure 1. 
Figure 1 
STUDY SCHEMATIC 


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3.2 
Visits 
Patients will attend a Screening Visit up to 4 weeks (28 days) prior to the Baseline Visit to 
determine eligibility for the study. During the study, patients will attend clinic visits at 
Baseline/Visit 1 (Day 1), Week 2/Visit 2 (Day 15), Week 3/Visit 3 (Day 22), Week 6/Visit 4 (Day 
43), Week 8/Visit 5 (Day 57), Week 9/Visit 6 (Day 64) and Week 12/Visit 7/Early Termination 
Visit (Day 85). Patients will also receive telephone follow-up calls at Days 8 and 50 to inquire 
about AEs and study drug compliance. In addition, post study exit follow-up telephone calls will 
be made daily on Days 86 to 90 to assess any changes in health (i.e., AEs) and medication (i.e., 
concomitant medications). 
The assessments planned for Visit 7 should be performed in the event of a patient withdrawing 
prematurely from the study. In this case, the visit is referred to as the “Early Termination Visit.” 
The duration of each patient’s participation in this study will be approximately 12 weeks 
(maximum of 17 weeks including Screening phase and post study exit telephone calls for 5 days). 


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4 Study Population 
It is estimated that approximately 120 patients will participate in the study at approximately 
15 centers in the US. 
Eligible patients for this study will be adult outpatients (between 18 and 60 years of age) who are 
diagnosed with schizophrenia, are clinically stable, in a residual (non-acute) phase of illness, and 
meet all the inclusion criteria and none of the exclusion criteria. Patients enrolled in the study 
will have been treated with a second generation antipsychotic (SGA) agent for at least 3 months 
(90 days) and on a stable dose for 1 month (30 days) prior to the Screening Visit and maintain the 
same dose throughout the course of the study (includes no change from Screening to 
Baseline/Visit 1 [Day1]). Approximately 160 patients will need to be screened (assuming a 25% 
screen failure rate) in order to randomize approximately 120 patients.  
The diagnosis of residual schizophrenia will be based on the Diagnostic and Statistical Manual of 
Mental Disorders, 4th edition, Text Revision (DSM-IV-TR).  
An initial diagnostic assessment will be performed by the Investigator to assess if the patient meets 
diagnostic criteria for schizophrenia according to the DSM-IV-TR using the Mini International 
Neuropsychiatric Interview (M.I.N.I.) version 6.0 (Appendix 3), all medical records, interviews by 
clinicians, and when appropriate, interviews with family or other informants. The diagnosis of 
schizophrenia will be confirmed by the Investigator.  
4.1 
Inclusion Criteria 
1.
Males and females 18 to 60 years of age, inclusive, at time of informed consent.
2.
Patients who meet DSM-IV-TR diagnostic criteria for schizophrenia using the M.I.N.I.
version 6.0 and who meet DSM-IV-TR diagnostic criteria for residual schizophrenia.
3.
4.
If female of childbearing potential, patients must
a) have a negative urine pregnancy test (all females regardless of childbearing potential
will be required to submit a pregnancy test), and
b) not be nursing or planning a pregnancy for the duration of the study through 30 days
after the last dosing visit, and
c) be abstinent or willing to use a reliable method of birth control from the Screening
Visit, and continue with the same method until 28 days after the last dosing visit


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Reliable methods of contraception that meet the study requirements are: 
•
Intrauterine device
•
Vasectomized partner
•
Surgical sterilization (have had uterus and/or both ovaries removed, and/or have had
a bilateral tubal ligation)
•
Hormonal contraceptives (estrogen-containing birth control pills, vaginal ring, patch,
injections or implants)
•
The use of 2 barrier methods of contraception (ie, 2 of the following used together):
male condom with intravaginal spermicide, diaphragm with spermicide; cervical cap
with spermicide
Note: The mini pill (micro-dosed progesterone preparations that do not contain 
estrogen) is not an acceptable form of contraception for this study. 
Females of childbearing potential who are abstinent can enroll in the study.  
A female is considered of childbearing potential unless she is post-menopausal (i.e., 
history compatible with menopause [i.e., reported lack of menses for ≥ 12 months] and 
no other biological/surgical cause).   
All male patients must follow the same methods of birth control with partners of 
childbearing potential from the Screening Visit until 28 days after the last dosing visit, 
Visit 7/Early Termination Visit (Day 85). 
5.
Patients currently receiving atypical antipsychotics (oral and long acting intramuscular
injectables) within the dose guidance from the USPI for the treatment of schizophrenia
disorder (e.g., SGAs like olanzapine, risperidone, paliperidone, quetiapine, aripiprazole and
lurasidone) are eligible provided they have been treated with the medication for at least
3 months (90 days), the dose has been stable for at least 1 month (30 days) prior to the
Screening Visit (includes no change from Screening to Baseline/Visit 1 [Day1]), and there
has been no inpatient psychiatric hospitalization in the past 4 months prior to Screening.
6.
7.


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8.
Patients who are capable, according to the Investigator, and have signed and received a copy
of the ICF after the nature and risks of study participation had been fully explained to them.
9.
Patients must have a reliable informant as deemed appropriate by the investigator.
4.2 
Exclusion Criteria 
Patients will not be enrolled in the study if they meet any of the following criteria: 
1.
2.
Patients with current major depressive disorder (MDD) at the Screening Visit


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10.
Patients currently using anticholinergic medications or within 1 month (30 days) prior to
Baseline for treatment of AEs associated with antipsychotic medications.
15.
Patients who have had an inpatient psychiatric hospitalization within 4 months of Screening.
16.
Patients with clinically significant laboratory abnormalities (hematology, chemistry, and
urinalysis) or with safety values of potential clinical concern or with AST or ALT > 2 x ULN
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4.3 
Patient Withdrawal 
Patients will be advised verbally and in the ICF that they have the right to withdraw from the study 
at any time without prejudice or loss of benefits to which they are otherwise entitled. Patients may 
withdraw from the study at any time and for any reason, and are not obligated to provide the reason. 
The Investigator or Sponsor may discontinue a patient from the study in the event of an 
inter-current illness, AE, other reasons concerning the health or well-being of the patient, or in the 
case of lack of cooperation, non-compliance, protocol violation, or other administrative reasons. If 
a patient does not return for a scheduled visit, every effort should be made to contact the patient. 
In any circumstance, every effort should be made to document patient outcome, if possible. The 
Investigator should inquire about the reason for withdrawal, request the patient to return all unused 
investigational product (IP), and follow-up with the patient regarding any unresolved AEs.  
Any reason for withdrawal given (or the failure to provide a reason) must be recorded in the source 
documentation and on the patient’s electronic case report form (eCRF). 
Patients who present a QTcF > 500 msec (unless due to ventricular pacing) or a QTcF change from 
the pre-dose Baseline ECG of > 60 msec at any time after Baseline are to be withdrawn from the 
study. The QTcF values will be recorded and assessed for clinical significance. 
Patients who start a prohibited concomitant medication, psychotherapy, or somatic therapy (light 
therapy, repetitive transcranial magnetic stimulation, and other non-invasive brain stimulation 
techniques) during the study may need to be withdrawn from the study. The decision to withdraw 
the patient will be made on a case-by-case basis in conjunction with the MM. 
Patients who withdraw prior to study completion for any reason will be asked to return to the clinic 
to complete the Visit 7 (Early Termination) assessments. 
If the patient withdraws from the study and consent for disclosure of further information is 
withdrawn then no further evaluations may be performed and no additional data may be collected. 
The Sponsor may retain and continue to use any data collected before such withdrawal of consent. 
Patients who withdraw from the study will not be replaced. 
For information on termination of the study refer to Section 9.11. 


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5 Study Treatments 
5.1 
Treatments Administered 
All medication used in this study will be prepared, packaged, and labeled in accordance with Good 
Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, and applicable laws and regulations. 
5.1.1 
Description of Study Medications 
Clinical study medication will be provided as hard, 
 gelatin capsules 
. 
Three different capsule strengths will be provided, as follows: 
•
AVP-786-
 (d6-DM 
 mg/Q 
 mg)
•
AVP-786-34/4.9 (d6-DM 34 mg/Q 4.9 mg)
•
AVP-786 Placebo, with the same excipients as the study medication
5.1.2 
Composition of Study Medications 
AVP-786 and matching placebo will be supplied as a solid oral dosage form (gelatin capsule). 
AVP-786 will contain 
 mg or 34 mg of d6-DM in combination with 4.9 mg of Q. 
 
 


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Table 1 
Composition of Investigational Products 
Ingredient 
AVP-786 (d6-DM 
 mg/Q 
 mg) (mg) 
AVP-786 (d6-DM 
34 mg/Q 4.9 mg) (mg) 
Placebo 
(mg) 
d6-dextromethorphan hydrobromide 
34.0 
0 
Quinidine sulfate USP, EP 
4.9 
0 
Croscarmellose sodium NF, EP 
Microcrystalline cellulose NF, EP 
Colloidal silicone dioxide NF, EP 
Magnesium stearate NF, EP 
Total 
Capsule: 
Hard 
gelatin 
capsules,
 
(average weight) 
Total Weight 
EP = European Pharmacopoeia; NF = National Formulary; USP = United States Pharmacopoeia 
5.1.3 
Packaging 
The IP will be supplied as ready-packaged, blinded, pre-labeled, individually pre-packaged blister 
cards. Each blister card will contain enough study medication to last for 3 weeks, i.e., 48 capsules 
of 1 of the 2 active study medications or placebo. Each 3-week blister card will be clearly labeled 
to identify the morning and evening doses. 
5.1.4 
Labeling 
All labels will contain the protocol number, material ID number, product name (AVP-786), blister 
card number, an investigational drug warning, dosing instructions to take 1 capsule in the morning 
and 1 capsule in the evening, storage conditions, and company name. The blister card label will 
consist of 2 panels, with 1 detachable panel that will be removed and kept with the site’s study 
records (e.g., affixed to the study medication dispensing log page or patient source records) at the 
time of dispensing. Space is provided on both panels of the card label to record patient number, 
dispensing date and assigned treatment week. All IP labels comply with all applicable federal and 
local regulations. 
5.1.5 
Storage of Clinical Supplies 
Clinical supplies must be stored in compliance with label requirements in a secure place and kept 
at room temperature; 25 °C (77 °F) with excursions permitted to 15 °C - 30 °C (59 °F–86 °F). 


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5.1.6 
Study Medication Administration 
All patients will receive AVP-786 or matching placebo according to the material ID number 
assigned by an interactive response technologies (IRT) system randomization scheme. Designated 
staff at each site will dispense study medication. The patient will self-administer the study 
medication, except on visit days when study medication will be administered in the presence of 
site personnel. Patients are to be advised NOT to take the morning dose of study medication on 
the day of their study visits. When self-administering, patients will be instructed to take the study 
medication approximately every 12 hours orally with water (morning and evening).  
Stage 1:  At Baseline/Visit 1 (Day 1) and Visit 3 (Day 22), study medication will be dispensed and 
administered as follows:  
•
Baseline/Visit 1 (Day 1): AVP-786 or placebo patients will be dispensed a 3-week blister
card labeled for the morning and evening doses. Patients will be administered 1 capsule
from the AM blister card in the morning and 1 capsule from the PM blister card in the
evening, approximately 12 hours apart until their next scheduled visit (Visit 3 [Day 22]).
The cards will be assigned such that patients randomized to active treatment will escalate
the dose. All other patients (i.e., those remaining on placebo treatment) undergo a dummy
escalation (required to take cards in strict order) to maintain blinding.
•
Visit 3 (Day 22): AVP-786 or placebo patients will be dispensed a 3-week blister card
containing cards labeled for the morning and evening doses. Patients will be administered
1 capsule from the AM blister card in the morning and 1 capsule from the PM blister card
in the evening, approximately 12 hours apart until their next scheduled visit (Stage 2, Visit
4 [Day 43]).
Stage 2: At Visit 4 (Day 43) and Visit 6 (Day 64), study medication will be dispensed and 
administered as follows:  
•
Visit 4 (Day 43): AVP-786 or placebo patients will be dispensed a 3-week blister card
labeled for the morning and evening doses. Patients will be administered 1 capsule from
the AM blister card in the morning and 1 capsule from the PM blister card in the evening,
approximately 12 hours apart until their next scheduled visit (Visit 6 [Day 64]). The cards
will be assigned such that patients re-randomized from placebo to active treatment will
escalate the dose. All other patients (i.e., those remaining on AVP-786 treatment or placebo
treatment) will undergo a dummy escalation (required to take cards in strict order) to
maintain blinding.
•
Visit 6 (Day 64): AVP-786 or placebo patients will be dispensed a 3-week blister card
labeled for the morning and evening doses. Patients will be administered 1 capsule from
the AM blister card in the morning and 1 capsule from the PM blister card in the evening,
approximately 12 hours apart until their next scheduled visit (Visit 7 [Day 85]).


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All study medication will be supplied and administered in a double-blind manner throughout the 
entire duration of the study. 
5.2 
Accountability of Study Supplies 
5.2.1 
Receipt of Supplies 
IP will be shipped by the Sponsor direct to the study sites. 
The Investigator is responsible for maintaining an inventory of each shipment of IP received and 
comparing it with the accompanying Drug Accountability Report/Material Shipping Form. The 
Investigator will verify the accuracy of the information. All IP supplied is for use only in this study 
and should not be used for any other purpose. All blister card material ID numbers will also be 
recorded and tracked at the site using a drug accountability log. 
5.2.2 
Record of Dispensing 
Accurate recording of all IP dispensing for individual patients will be made in the appropriate 
section of the patient’s drug accountability records. This document will contain the following 
information: (i) the patient number to whom the drug was dispensed; (ii) the date(s) and quantity 
of the drug dispensed to the patient; and (iii) the blister card material ID number assigned to the 
patient via IRT system.  
Additionally, the detachable panel of the 2-panel label on each card will be removed and kept with 
the site’s study records (e.g., affixed to a study medication patient drug dispensing log page) at the 
time of dispensing. Space is provided on both panels of the card label to record patient number, 
dispensing date and visit week.  
5.2.3 
Unused Supplies 
At the end of the study, all unused investigational supplies must be inventoried on a drug 
accountability log and returned to the Sponsor or its representative, along with a completed and 
signed Drug Accountability Report/Material Shipping Form. If any study medication is lost or 
damaged, it should be indicated on the form. 
5.3 
Methods of Assigning Patients to Treatment Groups 
5.3.1 
Randomization 
Upon entry into the study (after ICF is signed at the Screening Visit), all patients will be assigned 
a patient number. 
 
  


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Stage 1 
Eligible patients will be randomized into the study in a 
 (active:placebo) ratio to receive either 
AVP-786 capsules or matching placebo capsules at Baseline/Visit 1 (Day 1, Stage 1) in a double-
blind manner according to a randomization scheme devised by Avanir or its representative and 
managed within an IRT system.  
Stage 2 
Re-randomization will occur for patients who were assigned to placebo in Stage 1. The patient 
number will not be re-assigned; it will remain the same in both stages of the study. 
1. Patients who receive placebo in Stage 1 will be further stratified into 2 sub-groups
(“responders” and “non-responders”) based on their treatment responses. Patients will be
considered “responders” if their percent of change in 
from Baseline. Patients who do not meet this criterion will be considered “non-responders.”
Patients within each placebo sub-group will be re-randomized in a 
 (active:placebo) ratio to
receive either AVP-786 or matching placebo capsules.
2. Patients who receive placebo and who drop out early in Stage 1 will also be assigned a re-
randomization treatment in the same manner as the other placebo patients. Their “responders”
and “non-responders” status will be based on their treatment responses using measurements at
their Early Termination Visit.
3. Patients who receive AVP-786 in Stage 1 will not be re-randomized and will continue to
receive the same dose of AVP-786 for the entire duration of Stage 2.
5.3.2 
Blinding/Masking 
All study medication, including AVP-786 capsules and placebo capsules, are of identical 
appearance in order to maintain the integrity of the blind, including during dose escalation. Neither 
the Sponsor, patients, Investigators, nor other study personnel will be aware of a patient’s treatment 
assignment. In the event that it becomes medically necessary to identify which treatment a patient 
has received, the blind can be broken. In that event, the Investigator is to make all attempts to 
contact Avanir’s MM or representative to request the unblinding of a patient. The IRT manager is 
not required to be blinded, and he or she will have access to the study medication list and the 
randomization code. 


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5.4 
Patient Compliance 
Patients will be instructed to bring any used and unused study medication and empty blister packs 
to the clinic on Days 15, 22, 43, 57, 64, and 85 (Visits 2-7). For this study, compliance will be 
defined as when a patient takes at least 80% of their scheduled doses.  


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6 Study Assessments and Procedures 
6.1 
Efficacy 
Examples (for reference only) of all of the scales and questionnaires that will be used during the 
study can be found in the Appendices (Section 11).   
6.1.1 
16-Item Negative Symptom Assessment (NSA-16) 
The NSA-16 (Appendix 1) is considered a valid and reliable measure of the presence, severity, and 
range of negative symptoms associated with schizophrenia; it has high interrater and test–retest 
reliability across languages and cultures.50,51 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. These factors, assessed through a structured interview, are 
comprehensive and well-defined to help standardize assessment. As a truncated version of the 25-
item NSA, the NSA-16 still captures the multidimensionality of negative symptoms but can be 
completed in approximately 15 to 20 minutes.51 The NSA-452 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 evaluation will be performed at Screening (Day –28 to Day –1), Baseline/Visit 1 (Day 
1), Visit 3 (Day 22), Visit 4 (Day 43), Visit 6 (Day 64) and Visit 7/Early Termination Visit 
(Day 85).  
6.1.2 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS (Appendix 2) is a 30-item clinical scale that has been extensively used as a reliable 
and valid measure for negative symptom trials.50 Each item is scored for “1” (absent) to “7” 
(extremely severe). Three subscales can be derived: the Positive Subscale, the Negative Subscale 
and the General Psychopathology Subscale. Outpatients will need to identify a reliable informant 
(e.g., case manager, social worker, family member) who spends sufficient time with them to be 
able to provide information to PANSS raters.  
The PANSS subscale descriptions are provided below: 
•
Negative Subscale: N1-N7
•
Positive Subscale: P1-P7
•
General Psychopathology Subscale: G1-G16
•
Prosocial Factors:
o
G16. Active social avoidance
o
N2. Emotional withdrawal
o
N4. Passive/apathetic social withdrawal


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o
N7. Stereotyped thinking
o
P3. Hallucinatory behavior
o
P6. Suspiciousness/persecution
•
Marder Negative Factors:
o
N1. Blunted affect,
o
N2. Emotional withdrawal
o
N3. Poor rapport
o
N4. Passive/apathetic social withdrawal
o
N6. Lack of spontaneity and flow of conversation
o
G7. Motor retardation
o
G16. Active social avoidance
•
Excitement Component:
o
P4. Excitement
o
P7. Hostility
o
G4. Tension
o
G8. Uncooperativeness
o
G14. Poor Impulse Control
The PANSS evaluation will be performed at Screening (Day –28 to Day –1), Baseline/Visit 1 (Day 
1), Visit 3 (Day 22), Visit 4 (Day 43), Visit 6 (Day 64) and Visit 7/Early Termination Visit 
(Day 85). 
6.1.3 
Clinical Global Impression (CGI) Scales 
The CGI was developed to provide a brief, stand-alone assessment of the clinician's view of the 
patient's global functioning prior to and after initiating a study medication.53 The CGI provides an 
overall clinician-determined summary measure that takes into account all available information, 
including knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and 
the impact of the symptoms on the patient's ability to function. The CGI comprises 2 companion 
1-item measures, the CGI-S (Severity) and CGI-C (Change). The CGI forms can be completed in 
less than 1 minute by an experienced rater. 
6.1.3.1 Clinical Global Impression - Severity (CGI-S) 
The CGI-S (Appendix 5) is a 7-point scale that requires the clinician to rate the severity of the 
patient's illness at the time of assessment, relative to the clinician's past experience with patients  


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who have the same diagnosis.54 Considering total clinical experience, a patient 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 
patients.  
The CGI-S evaluation will be performed at Baseline/Visit 1 (Day 1), Visit 4 (Day 43) and 
Visit 7/Early Termination Visit (Day 85).     
6.1.3.2 Clinical Global Impression - Change (CGI-C) 
The CGI-C (Appendix 6) is a 7-point scale that requires the clinician to rate the change of the 
patient’s condition at the time of assessment, relative to the clinician’s past experience with the 
patient’s condition at admission. Considering total clinical experience, a patient 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.  
The CGI-C evaluation will be performed at Visit 4 (Day 43) and Visit 7/Early Termination Visit 
(Day 85).  At Day 43 (Visit 4), the CGIC will be completed to assess change from the Baseline 
Visit (Day 1). At Day 85 (Visit 7), the CGIC will be completed to assess change from Day 43 
(Visit 4) and change from the Baseline Visit (Day 1). 
6.1.3.3 Patient Global Impression – Change (PGIC) 
The PGIC (Appendix 4) is a 7-point (1–7), patient-rated scale used to assess treatment response 
as: very much improved, much improved, minimally improved, no change, minimally worse, much 
worse, or very much worse.  
The PGIC evaluation will be performed at Visit 4 (Day 43) and Visit 7/Early Termination Visit 
(Day 85).     
6.1.4 
Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS (Appendix 7) is a 9-item scale derived from the Hamilton Depression Scale (Ham-D) 
that is designed to assess depression specifically in patients with schizophrenia.55 Unlike the Ham-
D, the CDSS does not contain depressive symptoms that overlap with negative symptoms of 
schizophrenia, such as anhedonia and social withdrawal. The CDSS has shown excellent 
psychometric properties. Each item on the scale is scored as 0, Absent; 1, Mild; 2, Moderate; or 3, 
Severe. The CDSS score 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 evaluation will be performed at Screening (Day –28 to Day –1), Baseline/Visit 1 
(Day 1), Visit 3 (Day 22), Visit 4 (Day 43), Visit 6 (Day 64) and Visit 7/Early Termination Visit 
(Day 85).     


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6.1.5 
 Measurement and Treatment Research to Improve Cognition in 
Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) 
The MCCB (Appendix 8) is the standard tool for assessing cognitive change in trials of cognitive-
enhancing agents in schizophrenia. The MCCB56 is intended to provide a relatively brief evaluation 
of key cognitive domains relevant to schizophrenia and related disorders. The MCCB includes 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 evaluation will be performed at Screening (Day –28 to Day –1), Baseline/Visit 1 (Day 
1), Visit 4 (Day 43) and Visit 7/Early Termination Visit (Day 85). The MCCB should be conducted 
at approximately the same time of day (+/- 2 hours) and preferably in the AM. Alternate versions 
of the battery will be used at different visits to decrease the learning confound.  
6.1.6 
Effort Expenditure for Reward Task (EEfRT) 
The Effort Expenditure for Rewards Task EEfRT57 is a multi-trial computerized task in which 
participants are given an opportunity on each trial to choose between 2 tasks that differ in difficulty 
level and are associated with varying levels of monetary reward. This task examines probabilistic 
learning in response to variable reward schedules and effort expended (button pushing) for reward. 
Probability is manipulated in the EEfRT, because like mobilization of effort, probability 
discounting appears to be highly predictive of negative symptoms. Additionally, the inclusion of a 
probability manipulation improves the overall ecological validity of the task, as most real-world 
choices that require motivation are usually associated with some level of uncertainty in the 
outcome. The EEfRT reliably measures drug effects on willingness to expend effort in relation to 
amount of reward or probability of reward. For example, amphetamine increased effort in response 
to low- and moderate probability rewards.58 Whereas reward salience and behavioral response have 
been linked to dopamine release in the striatum, glutamatergic input to midbrain dopamine neurons 
via NMDA receptors is also required for reward conditioning.59 We will use the ratio of hard task 
choices with moderate probability reward as our outcome measure for negative symptoms. 
The EEfRT evaluation will be performed at Baseline/Visit 1 (Day 1), Visit 4 (Day 43) and 
Visit 7/Early Termination Visit (Day 85).   


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6.2 
Pharmacokinetics (PK) 
At Baseline/Visit 1 (Day 1, post-dose), Visit 4 (Day 43) and Visit 7/Early Termination Visit 
(Day 85) all patients will have plasma samples collected between 2 and 3 hours after the morning 
dose of study medication for analysis of study medication (d6-DM, its metabolites, and Q 
concentration levels). The time when the patient was administered the dose of study medication 
and the time of the blood draw will be recorded on the eCRF. Plasma samples will be separated by 
centrifugation and then stored in accordance with the study lab manual until assayed at the 
analytical unit. 
6.4 
Safety 
6.4.1 
Adverse Events 
6.4.1.1 Definitions 
An AE is any untoward medical occurrence or unintended change (including physical, 
psychological, or behavioral) from the time ICF is signed, including inter-current illness, which 
occurs during the course of a clinical study after treatment has started, whether considered related 
to treatment or not. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. Changes 
associated with normal growth and development that do not vary in frequency or magnitude from  


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that ordinarily anticipated clinically are not AEs (e.g., onset of menstruation occurring at a 
physiologically appropriate time). 
Clinical AEs should be described by diagnosis and not by symptoms when possible (e.g., cold, 
seasonal allergies, instead of “runny nose”). 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol and higher than known therapeutic doses. An overdose must be reported 
irrespective of outcome even if toxic effects were not observed. 
AEs will be graded on a 3-point scale and reported in detail as indicated on the eCRF: 
Mild: 
easily tolerated, causing minimal discomfort and not interfering with normal 
everyday activities 
Moderate: 
sufficiently discomforting to interfere with normal everyday activities 
Severe: 
incapacitating and/or preventing normal everyday activities 
The relationship of each AE to study medication should be determined by the Investigator using 
the following explanations: 
Not related: 
the event is clearly related to other factors such as the patient’s clinical state, 
therapeutic interventions, or concomitant medications administered to the 
patient 
Unlikely Related: 
the event is most likely produced by other factors such as the 
patient’s clinical state, therapeutic interventions, or concomitant 
medications administered to the patient; and does not follow a known 
response pattern to the study medication 
Possibly Related: 
the event follows a reasonable temporal sequence from the time of 
drug administration; and/or follows a known response pattern to the study 
medication; but could have been produced by other factors such as the 
patient’s clinical state, therapeutic interventions, or concomitant 
medications administered to the patient 
Related: 
the event follows a reasonable temporal sequence from the time of drug 
administration; and follows a known response pattern to the study 
medication; and cannot be reasonably explained by other factors such as the 
patient’s clinical state, therapeutic interventions, or concomitant 
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6.4.1.2 Serious Adverse Events 
A Serious Adverse Event (SAE) is any AE occurring at any dose that results in any of the following 
outcomes: 
1. Death
2. Life-threatening experience (that places the patient, in the view of the initial reporter,
at immediate risk of death from the AE as it occurred, i.e., it does not include an AE
that, had it occurred in a more severe form, might have caused death)
3. Persistent or significant disability/incapacity (disability is a substantial disruption of
a person’s ability to conduct normal life functions)
4. In-patient hospitalization or prolongation of hospitalization
5. Congenital anomaly/birth defect
Important medical events that may not result in death, or be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient or require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. 
The terms “cancer” and “overdose” may not always be considered to be SAEs, but if a patient 
experiences cancer or overdose, they are still reportable as AEs. 
Pregnancy is not considered to be an AE or an SAE, unless a complication occurs that meets the 
requirements for an AE or SAE, but must be reported on a pregnancy report form. Females who 
are pregnant or likely to become pregnant are excluded from this study. In the event a patient 
becomes pregnant during the study, study medication must be discontinued, a pregnancy report 
form must be completed to capture potential drug exposure during pregnancy, and the pregnancy 
must be reported within 24 hours of notice. Any pregnant patient must be followed until the 
outcome of 
her 
pregnancy 
is 
known 
(i.e., 
normal 
delivery, 
abnormal 
delivery, 
spontaneous/voluntary/therapeutic abortion). The pregnancy (i.e., the mother and the fetus) must 
be followed up through delivery with regard to outcome.  
A pregnancy report form must also be completed in the event that a female partner of a male patient 
becomes pregnant within 30 days after his last dose of study medication or study completion, 
whichever is greater.  
The term ‘severe’ is a measure of intensity; thus a severe AE is not necessarily serious. For 
example, nausea of several hours duration may be rated as severe, but may not be clinically serious. 


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6.4.1.3 Reporting 
Patients will be queried regarding AEs starting with the Baseline Visit (Visit 1, Day 1) until the 
end of the study (Days 1, 14, 22, 43, 57, 64, and 85 [Visits 1–5 including the 2 telephone follow-
up calls at Day 14 and Day 50, and the post-study follow-up calls at Days 85 through 90]). The 
Investigator will assess and record all reported AEs. Any AE newly reported after receiving the 
last dose of study medication and up until 30 days after receiving the last dose of study medication 
will be followed up until resolution (patient’s health has returned to his/her baseline status or all 
variables have returned to normal) or until stabilization of the event has occurred (the Investigator 
does not expect any further improvement or worsening of the event). 
A death occurring during the study, or which comes to the attention of the Investigator within 
30 days after stopping the treatment whether considered treatment-related or not, must be reported 
to the Sponsor. 
For all SAEs, including an abnormal laboratory test value, the Investigator should consult with 
Avanir’s MM as needed and report any SAE by fax/e-mail form no later than 24 hours after 
becoming aware of the event. Subsequently, the SAE must be assessed for the following details: 
seriousness of event, start date, stop date, intensity, frequency, relationship to test drug, action 
taken regarding test drug, treatment required, and outcome to date. These details must be recorded 
on the clinical study AE Form that is provided. This form should be transmitted by fax and the 
details given by telephone to the contact numbers below. 
SAE reporting by FAX or e-mail correspondence 
FAX: 
 
E-mail: 
 
SAE hotline (24-hour/7 days a week) 
Phone: 
 
Such preliminary reports will be followed by detailed descriptions later, which may include copies 
of hospital case reports, autopsy reports, and other related documents when requested. 
The IRB will be notified of such an event in writing as soon as is practical in compliance with 
federal and local regulations. 
6.4.1.4 Procedures to be Followed in the Event of Abnormal Test Values 
In the event of an unexplained abnormal laboratory test result found to be clinically significant by 
the Investigator, the test should be repeated and followed up until test values have either returned 
to the patient’s baseline (pretreatment) range and/or until an adequate explanation of the 
abnormality is found. 


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6.4.2 
Physical and Neurological Examinations 
The examination should include assessments of head, eyes, ears, nose, throat, lymph nodes, skin, 
extremities, respiratory, gastrointestinal, musculoskeletal, cardiovascular, and nervous systems. 
The physical and neurological examinations should be performed by the same person each time, 
whenever possible.  
Physical and neurological examinations abnormalities determined by the Investigator, including 
those that are determined to be clinically significant at Screening should be recorded as medical 
history.  
Any clinically significant changes in physical and neurological examination findings from the 
Screening examination should be recorded as AEs. 
Physical and neurological examinations will be performed at Screening (Day –28 to Day –1) and 
at the discretion of the Investigator at the subsequent visits. If a subsequent physical exam is 
performed after the Screening Visit, then the Investigator should document any clinically 
significant finding on the AE form.  
6.4.3 
Vital Signs, Weight, and Height 
At Screening (Day –28 to Day –1), orthostatic blood pressure (BP) and heart rate (HR) 
measurements will be performed. Supine BP and HR will be measured after a patient has rested 
for at least 5 minutes in the supine position. Each measurement will be taken twice in the same 
position and recorded. After the measurement of supine BP and HR, the patient will stand still for 
up to 3 minutes and a single measurement of standing BP and HR will be recorded within these 3 
minutes of standing. Respiratory rate (breaths/minute), body temperature, height and weight will 
also be recorded. 
Patients presenting with orthostatic hypotension (decrease of ≥ 20 mmHg in systolic blood 
pressure [SBP] or ≥ 10 mm Hg in diastolic blood pressure [DBP] upon postural change from supine 
to standing measured within 3 minutes) and/or postural tachycardia (HR increase 
≥ 30 beats/minute [bpm] from the supine measurements or HR ≥ 120 bpm on standing) meet 
exclusion criterion 3. 
At all subsequent visits, the supine/semi-recumbent SBP and DBP and HR (bpm), after at least 
5 minutes of rest, will be taken and recorded twice. Respiratory rate (breaths/minute), body 
temperature, and weight will also be recorded.  
The vital signs and weight will be recorded at Screening (Day –28 to Day –1), Baseline/Visit 1 
(Day 1), Visit 2 (Day 15), Visit 3 (Day 22), Visit 4 (Day 43), Visit 5 (Day 57), Visit 6 (Day 64), 
and Visit 7/Early Termination Visit (Day 85).   
Height will be recorded only at Screening (Day –28 to Day –1). 


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6.4.4 
Pregnancy Tests 
All female patients of childbearing potential should be instructed to use appropriate birth control 
methods for up to 4 weeks following the last dose of study medication (See Section 4.1). 
Urine pregnancy tests (beta-hCG) will be performed on all females regardless of childbearing 
potential at Baseline/Visit 1 (Day 1), Visit 3 (Day 22), Visit 4 (Day 43), Visit 6 (Day 64), and Visit 
7/Early Termination Visit (Day 85). At the Screening Visit, serum beta-hCG will be collected.  
6.4.5 
Clinical Laboratory Tests 
The following clinical laboratory assessments are to be performed at Screening 
(Day –28 to Day –1), Visit 4 (Day 43), and Visit 7/Early Termination Visit (Day 85). 
•
Blood chemistry (calcium, magnesium, phosphorus, glucose, sodium, potassium,
chloride, carbon dioxide, blood urea nitrogen [BUN], serum creatinine, uric acid,
albumin, total bilirubin, alkaline phosphatase, lactate dehydrogenase [LDH], aspartate
aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT], alanine
aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT], creatine kinase
[CK], gamma-glutamyl transferase [GGT], triglycerides, total protein, total cholesterol,
and glycosylated hemoglobin [HbA1c, at Screening and Visit 7]).
•
Hematology (red blood cell [RBC] count, hemoglobin, hematocrit, white blood cell
[WBC] count, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils,
platelet count, and morphology).
•
Urinalysis (pH, specific gravity, protein, glucose, ketones, bilirubin, urobilinogen,
nitrites, leucocytes, and blood). Microscopic analysis will be performed on those
samples that are positive for blood, protein, leucocyte esterase or nitrates.
•
Urine screen for presence of alcohol and substances of abuse - PCP, benzodiazepines,
cannabinoids, amphetamines, barbiturates, cocaine, and opiates. (Screening Visit only).
•
Thyroid function tests TSH, T3, T4 (Screening Visit only)
Any patients with clinically significant abnormal laboratory test results may be required by the 
MM to have a repeat test 1 week later or sooner, if medically indicated. Clinically significant 
laboratory abnormalities may be a basis for exclusion from study entry. Non-eCRF data including, 
but not limited to, laboratory tests and results, will be sent to the Sponsor, CRO, or representative 
by data transfer from the central laboratory. 


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6.4.6 
Electrocardiograms 
ECG equipment will be provided by the central reader. ECG data will be recorded at the study 
center and will include general findings, heart rate (beats/minute) QRS complex and PR and QTc 
intervals (milliseconds). Results will be provided by the central reader to the Investigators within 
72 hours and any significant findings will be reported within 24 hours. ECG abnormalities present 
at Screening will be recorded as medical history. Any changes from the ECG status at Screening 
that are deemed to be clinically significant by the Investigator should be recorded as AEs. Any 
clinically significant abnormal ECG should be discussed with the study MM and, if necessary, be 
repeated within a 1-week period. Non-eCRF data including, but not limited to, ECG tests and 
results, will be sent to the Sponsor, CRO, or representative by data transfer from the central reader. 
A resting 12-lead ECG will be performed at Screening (Day –28 to Day –1), Baseline/Visit 1 (Day 
1), Visit 4 (Day 43), and Visit 7/Early Termination Visit (Day 85). Triplicate ECGs will be 
performed at Screening. At Baseline/Visit 1 (Day 1) and Visit 4 (Day 43), 2 ECGs will be 
performed; one prior to study medication dosing and one 2 to 3 hours after dosing. 
6.4.7 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Appendix 9) is a low-burden measure of the spectrum of suicidal ideation and 
behavior that was developed by Columbia University researchers for the NIMH Treatment of 
Adolescent Suicide Attempters Study to assess severity and track suicidal events through any 
treatment. It is a clinical interview providing a summary of both ideation and behavior that can be 
administered during any evaluation or risk assessment to identify the level and type of suicidality 
present. The C-SSRS can also be used during treatment to monitor for clinical worsening.  
The C-SSRS evaluation will be performed at Screening (Day –28 to Day –1), Baseline/Visit 1 (Day 
1), Visit 3 (Day 22), Visit 4 (Day 43), Visit 6 (Day 64), and Visit 7/Early Termination Visit (Day 
85). 
6.4.8 
Simpson Angus Scale for Extrapyramidal Symptoms (SAS) 
The SAS (Appendix 10) is composed of 10 items and is used to assess pseudoparkinsonism. Grade 
of severity of each item is rated using a 5-point scale. SAS scores can range from 0 to 40. Signs 
assessed include gait, arm-dropping, shoulder-shaking, elbow rigidity, wrist rigidity, leg 
pendulousness, head dropping, glabella tap, tremor, and salivation. 
The SAS evaluation will be performed at Baseline/Visit 1 (Day 1), Visit 4 (Day 43) and 
Visit 7/Early Termination Visit (Day 85). 


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6.4.9 
Barnes Akathisia Scale (BAS) 
The BAS (Appendix 11) consists of items that assess the objective presence and frequency of 
akathisia, the level of an individual’s subjective awareness and distress, and global severity.  
The BAS is scored as follows: 
Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to 
Restlessness are rated on a 4-point scale from 0-3 and are summed yielding a total score ranging 
from 0 to 9. The Global Clinical Assessment of Akathisia uses a 5-point scale ranging from 0-4. 
The BAS evaluation will be performed at Baseline/Visit 1 (Day 1), Visit 4 (Day 43) and 
Visit 7/Early Termination Visit (Day 85). 
6.4.10 Abnormal Involuntary Movements Scale (AIMS) 
The AIMS (Appendix 12) is composed of 12 items and used to assess dyskinesia. Items related to 
severity of orofacial, extremity, and trunk movements, global judgment about incapacitation, and 
patient awareness are rated using a 5-point scale (0=none to 4=severe). Two items related to dental 
status are scored using “yes” or “no” responses.  
The AIMS evaluation will be performed at Baseline/Visit 1 (Day 1), Visit 4 (Day 43) and 
Visit 7/Early Termination Visit (Day 85). 
6.5 
Schedule of Evaluations and Procedures 
A schedule of evaluations and procedures is provided in Table 2. 


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Table 2 
Study Schedule of Evaluations and Procedures 
Stage 1 
Stage 2 
Procedure 
Visit: 
Screening 
Baseline 
Visit 1 
Telephone7
Visit 22 
Visit 31
Visit 42
Telephone7
Visit 52 
Visit 61
Visit 7/ 
ET 2,4 
Post Exit 
Telephone7 
Study Day: 
Day -28 to -7 
Day 1 
Day 8 
Day 15 
Day 22  
Day 43 
Day 50
Day 57 
Day 64 
Day 85 
Day 86-90 
Study Week: 
Week -4 to -1 
Week 1 
Week 2 
Week 3 
Week 6 
Week 7 
Week 8 
Week 9 
Week 12 
Informed Consent Form 
signed 
X 
 
X 
X 
Medical History 
X 
M.I.N.I. Exam 
X 
Inclusion and Exclusion  
X 
X 
Randomization / 
(re-randomization) 
X 
X 
Physical Examination 
X 
Resting 12-lead ECG 
X6
X6 
X6 
X6 
Chemistry, Hematology, and 
Urinalysis3  
X 
X 
X 
Pregnancy Test3
X 
X 
X 
X 
X 
X 
 
X5 
Plasma Antipsychotic Levels 
X 
X 
X 
PK and
 
X5
X5
X5 
Review of Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Vital Signs/Weight9 
X 
X 
X 
X 
X 
X 
X 
X 
NSA-16 
X 
X 
X 
X 
X 
X 
PANSS 
X 
X 
X 
X 
X 
X 
MCCB10 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
CDSS 
X 
X 
X 
X 
X 
X 
CGI-C 
X 
X 
PGIC 
X 
X 
RDoC Task (EEfRT) 
X 
X 
X 
Side Effects Scales  
(AIMS, BAS, SAS) 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Medication 
X 
X 
X 
X 
Dose in Clinic 
X 
X 
X 
X 
X 
X 
X 
Review and/or Return 
Unused Study Medication 
X8
X 
X 
X 
X8
X 
X 
X 
1 
Visits 3 and  6 have a +3 day window. 
2 
Visits 2, 4, 5, and 7 have a +/- 3 day window. 
3 
Urinary (beta-hCG) test will be performed for all females regardless of of childbearing potential (serum beta-hCG at Screening only). Fasting glucose and lipids will be 
measured at Screening, Visit 4 and Visit 7. 
4 
Final visit or Early Termination Visit for patients who withdraw prior to study completion. 
5 
PK blood draws will be taken 2-3 hours post-dose for Baseline and Visits 4 and 7.
 
6 
Electrocardiogram will be performed prior to dosing and 2-3 hours post-dosing for Visits 1 and 4. Post-dose only for Visit 7. Triplicate ECGs at Screening only. 
7 
Telephone call will have a +3 day window. Post study exit calls will be daily for 5 days to assess any changes in health (AEs)/concomitant medications. 
8 
Patient will be asked if they have taken their medications as directed during telephone calls at Days 8 and 50. 
9 
Height will be measured at Screening only. 


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10 
The MCCB should be conducted at approximately the same time of day (+/- 2 hours) and preferably in the AM. After the Screening Visit, patients who use 
sedatives/hypnotics or benzodiazepine medications on a prn basis should not take any of these medications the day of, or the day before, the assessment of cognitive 
function by MCCB. Patients who are on stable dose regimens of sedatives/hypnotics or benzodiazepine medications should take their medication as prescribed. 
6.5.1 
Description of Study Procedures 
Patients will be seen in the clinic for a Screening Visit within 28 days of dosing (Day 1) to assess 
eligibility for the study. Patients will be randomized after eligibility is confirmed on Day 1. 
At certain visits throughout the study, site staff will be required to enter information into the IRT 
system. Further instructions will be provided in the IRT Site Manual. 
6.5.1.1 Screening Visit (Days –28 to –1) 
The following procedures will be performed at Screening (within 28 days prior to Day 1): 
1. The Investigator or delegated site staff will provide the patients with informed consent
documents and will explain the rationale for the study, providing ample time for patients
to ask questions.
2. Authorization form completed and patient information will be entered into 
.
3. Patients will be assessed for inclusion and exclusion criteria.
4. Medical history, including patient demographics, and any concomitant medications use
(including over-the-counter [OTC] medications, vitamins, and supplements) will be
reviewed and recorded.
5. Psychiatric history will be recorded and M.I.N.I. exam will be conducted.
6. Physical and neurological examination will be conducted.
7. Orthostatic BP and HR measurements will be performed. Supine BP and HR will be
measured after a patient has rested for at least 5 minutes in the supine position. Each
measurement will be taken and recorded twice. After the measurement of supine BP and
HR, the patient will stand still for up to 3 minutes and a single measurement of standing
BP and HR will be recorded within these 3 minutes of standing. Respiratory rate
(breaths/minute), body temperature, height and weight will also be recorded.
8. In addition, the following tests will be completed:
a) NSA-16
b) PANSS
c) MCCB
d) CDSS
e) C-SSRS
9. A serum pregnancy test will be performed on all females regardless of childbearing
potential.


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10. A blood and/or urine specimen will be collected for:
a) Clinical laboratory assessments
b) Plasma antipsychotic levels
11. Triplicate 12-lead ECGs will be performed at Screening.
12. Patient information will be recorded in the IRT system.
Patient Instructions 
The Investigator will give patients detailed instructions regarding study procedures. They will also 
be instructed to consult with the study site prior to taking any non-study medications. These 
requirements will be reviewed in person, and written instructions may also be provided to the 
patient in addition to the informed consent per Investigator discretion.  
The Investigator will query patients at the end of each visit to be certain they understand what is 
required of them. 
6.5.1.2 Visit 1 (Baseline Visit, Day 1); Stage 1 
The Baseline/Visit 1 (Day 1) visit should occur in the morning.  
Before dosing the following procedures will be performed at Baseline/Visit 1 (Day 1): 
1. Inclusion/exclusion criteria will be reviewed.
2. Supine/semi-recumbent BP and HR (measured twice); respiratory rate (breaths/minute),
body temperature, and weight will also be recorded.
3. Patients will be queried regarding AEs and concomitant medication use (including OTC
medications, vitamins, and supplements). In addition, confirmation that patient did not
take prn sedatives/hypnotics or benzodiazepine medications on date of visit or day before.
4. In addition:
a) NSA-16
b) PANSS
c) MCCB
d) CGI-S
e) CDSS
f)
EEfRT
g) C-SSRS
h) AIMS


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i)
BAS
j)
SAS
k)
5. A urine pregnancy test will be performed on all females regardless of childbearing
potential.
6. A blood specimen will be collected for 
 (shipped frozen).
7. A resting 12-lead ECG will be performed prior to dosing.
8. Visit information along with PANSS total score will be entered in the IRT system
Patients will be randomized once it is determined that they satisfy all of the inclusion and none of 
the exclusion criteria (on the basis of the Screening and Baseline assessments described above) 
and will be assigned with a study medication card number via IRT. 
Study Medication Dosing: 
The FIRST dose of study medication will be administered at the clinic regardless of the time of 
day.  
After Dosing: 
1. A PK sample will be collected between 2 and 3 hours post dosing.
2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) post dosing.
3. Sufficient study medication will be dispensed for a 21-day (3-week) treatment period.
Patient Instructions 
The Investigator will give patients detailed instructions regarding study procedures. They will also 
be instructed to consult with the study site prior to taking any non-study medications. These 
requirements will be reviewed in person, and written instructions will be provided to the patient. 
Patients will be instructed to take the study medication BID (1 capsule from the blister labeled AM 
in the morning and 1 capsule from the blister labeled PM in the evening, approximately every 
12 hours) for 21 days (3 weeks). Patients will also be instructed to bring to the clinic any used and 
unused study medication at each study visit.  
The Investigator will query patients at the end of each visit to be certain they understand what is 
required of them. 
6.5.1.3 Telephone Follow-up (Day 8); Stage 1 
Patients will be called and asked if they have had any changes in their medications, experienced 
any AEs and have taken their study medication as instructed since the Baseline Visit. Patients  


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should also be asked if they have any questions/concerns regarding adhering to the medication 
regimen. They will also be asked to return their study medication cards at the next visit. 
6.5.1.4 Visit 2 (Day 15 ± 3 day window), Week 2; Stage 1 
The visit should occur within the 3-day window as described. The following procedures will be 
performed: 
1. Supine/semi-recumbent BP and HR (measured twice); respiratory rate (breaths/minute),
body temperature, and weight will also be recorded.
2. AEs and concomitant medications
3. C-SSRS
4. Study medication review
5. Study medication will be administered from the AM strip of the blister card brought in by
the patient.
Patients will be asked to return their study medication cards for review by the site during this visit. 
Sites will check for dosing compliance and return the study medication cards to the patient to use 
until the next scheduled visits. (New medication cards should not be dispensed at this visit).  
6.5.1.5 Visit 3 (Day 22 + 3-day window), Week 3; Stage 1 
The visit should occur in the morning. The patient is advised NOT to take the morning dose of 
study medication prior to the clinic appointment. If the patient has taken the morning dose on the 
same day as the visit then the patient should be asked to return the following day to complete the 
study visit procedures. 
Before dosing the following procedures will be performed: 
1. Supine/semi-recumbent BP and HR (measured twice); respiratory rate (breaths/minute),
body temperature, and weight will also be recorded.
2. AEs and concomitant medications
3. A urine pregnancy test will be performed on all females regardless of childbearing
potential.
4. In addition:
a) NSA-16
b) PANSS
c) CDSS
d) C-SSRS


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5. Returned and unused study medication will be accounted for compliance.
6. Visit information along with PANSS total score will be entered in the IRT system.
Study Medication Dosing: 
The FIRST dose of NEW study medication will be administered from the assigned blister pack at 
the clinic regardless of the time of day.  
After Dosing: 
1. Sufficient study medication will be dispensed for a 21-day (3-week) treatment period.
Patient Instructions 
Patients will be instructed to take the study medication BID (1 capsule from the blister labeled AM 
in the morning and 1 capsule from the blister labeled PM in the evening, approximately every 
12 hours) for 21 days (3 weeks). Patients will also be instructed to bring to the clinic any used and 
unused study medication at each study visit. 
The Investigator will query patients at the end the visit to be certain they understand what is 
required of them. 
6.5.1.6 Visit 4 (Day 43 ± 3-day window), Week 6; Stage 1 
The visit should occur in the morning. The patient is advised NOT to take the morning dose of 
study medication prior to the clinic appointment. If the patient has taken the morning dose on the 
same day as the visit then the patient should be asked to return the following day to complete the 
study visit procedures. 
Before dosing the following will be performed: 
1. Supine/semi-recumbent BP and HR (measured twice); respiratory rate (breaths/minute),
body temperature, and weight will also be recorded.
2. AEs and concomitant medications
3. A urine pregnancy test will be performed on all females regardless of childbearing
potential.
4. In addition:
a) NSA-16
b) PANSS
c) MCCB
d) CGI-S
e) CDSS


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f)
CGI-C
g) PGIC
h) EEfRT
i)
C-SSRS
j)
AIMS
k) BAS
l)
SAS
m)
5. Returned and unused study medication will be accounted for compliance.
6. A resting 12-lead ECG will be performed prior to dosing.
7. Visit information along with PANSS total score will be entered in the IRT system
Patients will either continue to use AVP-786 or be re-randomized to receive either AVP-786 or 
matching placebo (see Section 3.1). 
Study Medication Dosing: 
The FIRST dose of NEW study medication will be administered from the assigned blister pack at 
the clinic regardless of the time of day.  
After Dosing: 
1. A blood/urine specimen will be collected for:
a) Clinical laboratory assessments
b) Plasma antipsychotic levels
c) PK sample 2-3 hours (± 15 minutes) post dosing (shipped frozen)
2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) post dosing.
3. Sufficient study medication will be dispensed for a 21-day (3-week) treatment period.
Patient Instructions 
Patients will be instructed to take the study medication BID (1 capsule from the blister card labeled 
AM in the morning and 1 capsule from the blister card labeled PM in the evening, approximately 


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every 12 hours) for 21 days (3 weeks). Patients will also be instructed to bring to the clinic any 
unused study medication at each study visit.  
The Investigator will query patients at the end the visit to be certain they understand what is 
required of them. 
6.5.1.7 Telephone Follow-up (Day 50); Stage 2 
Patients will be called and asked if they have had any changes in their medications, experienced 
any AEs and have taken their study medication as instructed since the Baseline Visit. Patients 
should also be asked if they have any questions/concerns regarding adhering to the medication 
regimen. They will also be asked to return their study medication cards at the next visit. 
6.5.1.8 Visit 5 (Day 57 ± 3 day window); Week 8; Stage 2 
The visit should occur within the 3-day window as described. The following procedures will be 
performed: 
1. Supine/semi-recumbent BP and HR (measured twice); respiratory rate (breaths/minute),
body temperature, and weight will also be recorded.
2. AEs and concomitant medications
3. C-SSRS
4. Study medication review
5. Study medication will be administered from the AM strip of the blister card brought in by
the patient.
Patients will be asked to return their study medication cards for review by the site during this visit. 
Sites will check for dosing compliance and return the study medication cards to the patient to use 
until the next scheduled visits. (New medication cards should not be dispensed at this visit).  
6.5.1.9 Visit 6 (Day 64 + 3-day window); Week 9; Stage 2 
The visit should occur in the morning. The patient is advised NOT to take the morning dose of 
study medication prior to the clinic appointment. If the patient has taken the morning dose on the 
same day as the visit then the patient should be asked to return the following day to complete the 
study visit procedures. 
Before dosing the following procedures will be performed: 
1. Supine/semi-recumbent BP and HR (measured twice); respiratory rate (breaths/minute),
body temperature, and weight will also be recorded.
2. AEs and concomitant medications


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3. A urine pregnancy test will be performed on all females regardless of childbearing
potential. 
4. In addition:
a) NSA-16
b) PANSS
c) CDSS
d) C-SSRS
4. Returned and unused study medication will be accounted for compliance.
5. Visit information along with PANSS total score will be entered in the IRT system
Study Medication Dosing: 
The FIRST dose of NEW study medication will be administered from the assigned blister pack at 
the clinic regardless of the time of day.  
After Dosing: 
1. Sufficient study medication will be dispensed for a 21-day (3-week) treatment period.
Patient Instructions 
Patients will be instructed to take the study medication BID (1 capsule from the blister card labeled 
AM in the morning and 1 capsule from the blister card labeled PM in the evening, approximately 
every 12 hours) for 21 days (3 weeks). Patients will also be instructed to bring to the clinic any 
unused study medication at each study visit. 
The Investigator will query patients at the end the visit to be certain they understand what is 
required of them. 
6.5.1.10 Visit 7/Early Termination (Day 85 ± 3-day window), Week 12; Stage 2 
This visit will take place in the morning. 
The assessments scheduled for this visit are also to be performed if patients withdraw from the 
study early. In this case the visit is termed the “Early Termination Visit” and patients should 
attempt to return to the clinic 7 days after they were withdrawn if possible. If not within 7 days, 
patients should still make every attempt to return for a final exit visit. 
Before dosing the following will be performed: 
1. Supine/semi-recumbent BP and HR (measured twice); respiratory rate (breaths/minute),
body temperature, and weight will also be recorded.
2. AEs and concomitant medications


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3. A urine pregnancy test will be performed on all females regardless of childbearing
potential. 
4. In addition:
a) NSA-16
b) PANSS
c) MCCB
d) CGI-S
e) CDSS
f)
CGI-C (The CGIC will be completed to assess change from Day 43 [Visit 4] and
change from the Baseline Visit [Day 1]).
g) PGIC
h) EEfRT
i)
C-SSRS
j)
AIMS
k) BAS
l)
SAS
m)
5. Returned and unused study medication will be accounted for compliance.
6. Visit information along with PANSS total score will be entered in the IRT system
Study Medication Dosing: 
The LAST dose of study medication will be administered from the assigned blister pack at the 
clinic regardless of the time of day.  
After Dosing: 
1. A blood/urine specimen will be collected for:
a) Clinical laboratory assessments
b) Plasma antipsychotic levels
c) PK sample 2-3 hours (± 15 minutes) post dosing (shipped frozen)
2. A resting 12-lead ECG will be performed 2-3 hours (± 15 minutes) post dosing.


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3. At the last patient contact, site staff will access 
, enter the patient study ID and
the nature of the last contact (i.e., early termination or completer). 
6.5.1.11 Post Study Exit Daily Telephone Follow-up (Days 86-90); Stage 2 
Patients will be called daily for 5 days post the study exit visit and asked if they have had any 
changes in their health, experienced any AEs or changes to their medications since their final visit. 
Any AE previously reported and not yet resolved at the time of this visit, will be followed-up until 
resolution (patient’s health has returned to his/her baseline status or all variables have returned to 
normal) or until stabilization of the event has occurred (the Investigator does not expect any further 
improvement or worsening of the event). 
Any newly reported AE after receiving and up to 30 days after the last dose of study medication 
will be followed up until resolution (patient’s health has returned to his/her baseline status or all 
variables have returned to normal) or until stabilization of the event has occurred (the Investigator 
does not expect any further improvement or worsening of the event).  


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7 Data Management 
The Sponsor or designated representative (e.g., CRO) will perform the data management activities 
in accordance with the data management plan (DMP). The DMP will outline the systems and 
procedures to be used in the study. 
Clinical study data will be reported (captured) by study site personnel on eCRFs. An eCRF must 
be completed for every patient enrolled in the study. The eCRF data will be entered by trained 
study-site personnel and then reviewed for completeness and accuracy and electronically signed 
by the Investigator or authorized designee. All study-site personnel must use a password-protected 
user account to enter, review, or correct study data. Electronic signature procedures shall comply 
with the CFR Title 21 Part 11. Passwords will be strictly confidential. 
All eCRF data will be exported from the EDC system and transferred to the Sponsor or 
representative. The Sponsor or representative will also receive electronic transfers of non-eCRF 
data such as laboratory data from the central laboratory, ECG data from the central ECG reader, 
as well as other data from third-party vendors as appropriate. The electronic data format of all 
transfers will be agreed upon with the Sponsor or representative and documented in the DMP or 
vendor data transfer requirements document as appropriate. 
The clinical monitoring staff will perform source data verification (SDV) of the data recorded in 
the EDC system with source documents at the clinical study sites according to the DMP and clinical 
monitoring plan. The data will be subjected to consistency and validation checks within the EDC 
system with supplemental data reviews performed outside of the EDC system.   
Medical History and AEs will be coded using a current version of Medical Dictionary for 
Regulatory Activities (MedDRA), and concomitant medications using a current version of the 
World Health Organization (WHO) Drug Dictionary. The Sponsor or representative will perform 
a medical safety review of the coding. 
Completed eCRF images with a date- and time-stamped electronic audit trail indicating the user, 
the data entered, and any reason for change (if applicable) will be archived at the Investigator’s 
site and Sponsor’s site. 


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8 Statistical Methods 
8.1 
Analysis Populations 
Modified Intent-to-Treat (mITT) Population: The mITT population is defined as all randomized 
patients who had at least one post-Baseline NSA-16 efficacy assessment. The mITT population 
will be used for all analyses of efficacy. Patients will be included in the treatment group to which 
they were randomized, regardless of treatment received. 
Intent-to-Treat (ITT) Population: The ITT population includes all randomized patients. The ITT 
population will be used for exploratory efficacy analyses. 
Safety Population: The safety population includes all patients who received 1 or more doses of 
study treatment. The safety population will be used for all analyses of safety and patients will be 
included in the treatment group based on treatment received. 
8.2 
Demographic and Baseline Characteristics 
Baseline characteristics, such as demographics, will be summarized by treatment group for the ITT 
and mITT populations.  
8.3 
Efficacy Analysis 
The primary and secondary efficacy endpoints are assessed throughout the study. 
8.3.1 
Study Endpoints 
Efficacy Measures 
Primary Efficacy Measures: 
The primary efficacy measure is the NSA-16 total score. 
Secondary Efficacy Measures: 
Secondary efficacy measures include the following: 
•
PANSS total score, PANSS subscales (positive, negative, general psychopathology,
Marder negative factors, excitement component, and prosocial factors)
•
NSA-16 factor domains, global score, individual items, and NSA-4 (four NSA-16 items
include: 1) restricted speech quantity, 2) reduced emotion, 3) reduced social drive, and 4)
reduced interests, as well as an overall global rating of negative symptoms.)
•
Proportion of patients with a reduction of 20% or greater in the PANSS total score
•
MCCB composite score
•
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•
CDSS
•
EEfRT
8.3.2 
Primary Efficacy Analysis
The primary efficacy endpoint is the change from Baseline/Visit 1 to Week 6/Visit 4 (Day 43, 
Stage 1) and from Week 6/Visit 4 (Day 43) to Week 12/Visit 7(Day 85, Stage 2) on the NSA-16 
total score. The primary efficacy analysis will be based on the SPCD method using a weighted 
ordinary least square test statistics combining treatment effects from Stage 1 and 2.2,48 Data from 
Stage 1 placebo non-responders who are re-randomized into Stage 2 will be used to estimate Stage 
2 treatment effect. 
The null hypothesis is that there is no treatment effect in Stage 1 or Stage 2 and it will be tested 
against the alternative that there is a treatment effect in at least 1 of the 2 stages. The treatment 
effect in each stage will be estimated by using a likelihood-based linear mixed effects model 
repeated measures (MMRM) on observed data. The model will include fixed effects for treatment, 
visit, treatment-by-visit interaction, Baseline-by-visit interaction and Baseline value as a covariate. 
An unstructured covariance model will be used. 
8.3.3 
Secondary Efficacy Analyses 
Secondary efficacy endpoints include: change from Baseline to Week 6/Visit 4 (Day 43, Stage 1) 
and from Week 6/Visit 4 (Day 43) to Week 12/Visit 7 (Day 85, Stage 2) for the following efficacy 
measures: PANSS total score; PANSS subscales (positive, negative, general psychopathology, 
Marder negative factors, excitement component, and prosocial factors); NSA-16 (factor domains, 
global score, individual items, and NSA-4 factors); proportion of patients with 20% reduction in 
PANSS total score; MCCB composite score; CGI-S, CGI-C, and PCIG scores (measures change 
at post Baseline visits); CDSS; and EEfRT. These endpoints will be analyzed in a similar manner 
as the primary efficacy analysis.  
8.4 
 
 
  
8.5 
Plasma Antipsychotic Levels 
Plasma antipsychotic levels will be summarized descriptively. 


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8.6 
Safety and Tolerability Analysis 
Safety and tolerability will be assessed by the following measurements: AEs, vital signs, weight, 
urine pregnancy tests, clinical laboratory assessments, resting 12-lead ECGs, C-SSRS, AIMS, 
BAS, and SAS. 
Safety analyses will consist of data summaries for biological parameters and AEs. Safety analyses 
will be tabulated by treatment.  
8.6.1 
Adverse Events 
AEs will be coded using the MedDRA. The percentages of patients experiencing 1 or more AEs 
will be summarized by treatment, system organ class (SOC), deaths, nonfatal SAEs, AEs, AEs 
resulting in study discontinuation, and treatment-emergent AEs (TEAEs). TEAEs are those AEs 
that occur after the first dose of study medication up until 30 days after last dose.  
8.6.2 
Vital Signs and ECGs 
Summary statistics of absolute values and percentage change from Baseline for BP (diastolic and 
systolic), HR, respiratory rate, and ECG parameters will be provided. All values outside a pre-
defined normal range will be highlighted in the individual patient data listings. 
8.6.3 
Clinical Laboratory Values 
Laboratory parameters will be summarized via descriptive statistics and via shifts in results in 
respect to normal ranges between Baseline and end of treatment as increased, decreased, or no 
change.  
8.6.4 
Data and Safety Monitoring Board 
A data and safety monitoring board will not be used for this study. 
8.6.5 
Interim Analysis 
An interim analysis of efficacy is not planned; however, may be carried out. If so, the protocol will 
be amended to provide details. 
8.7 
Sample Size Justification 
Based on published studies such as Kane et al. (1988)1 and Buchanan, et al (2014),2 sample size 
calculations were performed assuming a bivariate normal distribution for the primary endpoint. 
 
  


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9 Administrative Procedures 
9.1 
Institutional Review Board Approval 
IRBs must meet the guidelines set out by the US FDA and conform to local laws and customs 
where appropriate. Written IRB approval for the protocol and the signed ICF must be obtained and 
transmitted to Avanir Pharmaceuticals or representative before the study can be initiated. The IRB 
must be informed of and approve all protocol amendments. The Investigator will ensure that this 
study is conducted in full conformance with the laws and regulations of the US (see Appendix 13 
Investigator Responsibilities). The complete text of the World Medical Association Declaration of 
Helsinki is given in Appendix 14. 
9.2 
Informed Consent Form 
The ICF will follow the principles outlined in the current version of the Declaration of Helsinki. 
For each patient found to be eligible for the study, informed consent will be obtained from the 
patient.  
The patients will be properly informed of the purpose of the study. The patients will be alerted to 
any anticipated AE that may be encountered with the study medication. A signed ICF will be 
obtained from all patients prior to patient entry into this study. Patients will be provided with a 
copy of their signed ICF. 
9.3 
Quality Assurance 
9.3.1 
Documentation 
For each process, evaluation, or test that generates study data but is not described in the protocol 
or eCRF, a written description of the data generation procedures shall be retained in the quality 
assurance section of the study files. In the case of routine clinical diagnostic procedures, only a 
copy of the relevant certification document is required. 
9.3.2 
Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
Investigator. This will include telephone calls and on-site visits. The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected. 
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol. As part of the data audit, source documents will be made available for review by the 
study monitor. The study monitor may periodically request review of the Investigator study file to 
assure the completeness of documentation in all respects of clinical study conduct. 
The study monitor will verify that each patient has proper consent documentation from the patient 
and/or patient’s authorized representative for study procedures and for the release of  


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medical records to the Sponsor, FDA, other regulatory authorities, and the IRB. The study monitor 
will also verify that assent was obtained for patients not capable of providing informed consent or 
that documentation is provided by the Investigator explaining why the patient was unable to 
provide assent. The Investigator or appointed delegate will receive the study monitor during these 
on-site visits and will cooperate in providing the documents for inspection and respond to inquiries. 
In addition, the Investigator will permit inspection of the study files by authorized representatives 
of the regulatory agencies. 
On completion of the study, the study monitor will arrange for a final review of the study files after 
which the files should be secured for the appropriate time period. 
9.3.3 
Medical Monitoring 
Throughout the course of the study, the MM may verify eligibility of all screened patients, will 
address any medical issues that might arise, clarify medical questions, review patient safety data 
(e.g., AE/SAE, laboratory, and ECG) and partner with the study team in the overall study 
management. The study medical monitoring plan will document additional details of the study 
medical oversight and monitoring. 
9.4 
Electronic Case Report Forms 
For each patient enrolled who has given informed consent, an eCRF must be completed and 
electronically signed by the investigator to certify that the data within each eCRF are complete and 
correct. This also applies to those patients who fail to complete the study. If a patient is withdrawn 
from the study because of a treatment-limiting AE, thorough efforts should be made to document 
the outcome. 
Any site personnel delegated responsibility for data entry, query resolution, or eCRF approval must 
complete training prior to accessing the eCRF. The EDC vendor will provide user-specific access 
to the live (production) eCRF once training completion has been confirmed and the account has 
been approved by the sponsor. Changes to the data once it has been initially saved will be tracked 
via audit trail and will require a reason for the change. The audit trail will also include who made 
the change and a date/time stamp. 
The eCRFs will be reviewed by the study monitor at the study site. Errors detected by subsequent 
in-house data review may necessitate clarification or correction of errors. All changes will be 
documented and approved by the investigator. 
All investigators will be provided with copies of the eCRFs for their site on a CD-ROM at the end 
of the study. 


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9.5 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Avanir, the Investigator agrees 
to keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, telephone calls reports). 
The records should be retained by the Investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Avanir should be prospectively notified. The study 
records must be transferred to a designee acceptable by Avanir, such as another Investigator, 
another institution, or to Avanir. The Investigator must obtain Avanir’s written permission before 
disposing of any records, even if retention requirements have been met. 
9.6 
Source Data 
The documents that will form the source data for the clinical study (e.g., patient charts, laboratory 
reports) must be defined and documented in the in-house study master file prior to the start of the 
study. Data on the eCRFs which will be checked against source data during monitoring visits must 
also be defined and documented in the in-house study master file including the percentage of each 
of the source data to be verified and the percentage of patients’ eCRFs to be monitored. 
9.7 
Data Handling 
The eCRF data will be entered by trained study-site personnel. Queries will be issued as outlined 
in the DMP and clinical monitoring plan and should be resolved by the investigational center in a 
timely manner. The eCRF data will be reviewed for completeness and accuracy and electronically 
signed by the Investigator or authorized designee.   
9.8 
Laboratory Procedures 
Each individual site laboratory will collect clinical laboratory samples for analysis. Instructions for 
specimen evaluation and transport to a central laboratory will be provided at the time of study 
initiation.  
9.9 
Guidelines for Good Clinical Practice 
Standards for GCP must be adhered to for all study-based procedures. 


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9.10 Conditions for Amending the Protocol 
Protocol modification to ongoing studies which could potentially adversely affect the safety of 
patients or which alter the scope of the investigation, the scientific quality of the study, the 
experimental design, dosages, duration of treatment, assessment variables, the number of patients 
treated, or patient selection criteria must be made only after appropriate consultation between an 
appropriate representative of Avanir and the Investigator. 
Protocol modifications must be prepared by a representative of Avanir or the Investigator, and 
reviewed and approved by Avanir. All major changes must be addressed and when appropriate, 
justified in the Background and/or Study Design section of the protocol. 
All protocol modifications must be reviewed and approved by the appropriate IRB in accordance 
with local requirements, before the revised edition can be implemented. Modifications which 
eliminate an apparent immediate hazard to patients do not require pre-approval by the IRB. 
9.11 Conditions for Terminating the Study 
Both Avanir and the principal Investigator reserve the right to terminate the study at the site at any 
time. Should this be necessary, the procedures to effect study termination will be arranged after 
review and consultation by both parties. In terminating the study, Avanir and the Investigator will 
assure that adequate consideration is given to the protection of the patient’s interests. 
9.12 Confidentiality of Study Documents and Patient Records 
The Investigator must assure that the patient’s anonymity will be maintained. On eCRFs or other 
documents submitted to Avanir, patients should not be identified by their names but by an 
identification code. 
The Investigator should keep a separate log of patient’s codes, names, and addresses. Documents 
not for submission to Avanir, for example, patients’ signed ICFs, should be maintained by the 
Investigator in strict confidence. 
9.13 Reports 
At the completion of the study, the Investigator shall provide the Sponsor with an adequate report 
shortly after completion of the Investigator's participation in the study as described in CFR Title 
21, Part 312.64. 
9.14 Publications 
It is anticipated that a report of this study will be published in the scientific literature by the 
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results from the study in any scientific journal, or other publication or by way of lecture without 
Avanir’s prior review and written consent.  
9.15 Audits/Inspections 
The Investigator should understand that source documents for this study should be made available 
to appropriately qualified personnel or designee(s) from Avanir or to health authority inspectors 
after appropriate notification. The verification of the eCRF data may be by direct inspection of 
source documents (where permitted by law) or through an interview exchange. 
The inspector from the regulatory authority will be especially interested in the following items: 
1. Visits from the Sponsor’s representatives
2. IRB approval(s)
3. Study medication accountability
4. Study protocol and amendments
5. ICFs of the patient (if capable of providing ICF, according to the Investigator) or patient’s
authorized representatives
6. Assent of the patients (if capable of providing assent, according to the Investigator)
7. Medical records supportive of eCRF data
8. Reports to the IRB and the Sponsor
9. Record retention
The Sponsor will be available to help Investigators prepare for an inspection. 


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10 REFERENCES 


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11 Appendices 
Appendix 13: Investigator Responsibility 
Appendix 14: World Medical Association Declaration Helsinki 


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Appendix 13: 
Investigator Responsibility 


Guidance for Industry
E6 Good Clinical Practice:
Consolidated Guidance
ICH
April 1996


Guidance for Industry
E6  Good Clinical Practice: 
Consolidated Guidance
Additional copies are available from:
 the Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research (CDER),
5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication,
Training, and Manufacturers Assistance (HFM-40)
Center for Biologics Evaluation and Research (CBER)
1401 Rockville Pike, Rockville, MD 20852-1448,
http://www.fda.gov/cber/guidelines.htm
(Fax) 888-CBERFAX or 301-827-3844
(Voice Information) 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
April 1996
ICH


13
(b) Changes increasing the risk to subjects and/or affecting significantly the
conduct of the trial (see section 4.10.2). 
(c) All adverse drug reactions (ADRs) that are both serious and
unexpected. 
(d)  New information that may affect adversely the safety of the subjects or
the conduct of the trial.
3.3.9  Ensuring that the IRB/IEC promptly notify in writing the
investigator/institution concerning:
(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.
3.4
Records
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists,
lists of occupations/affiliations of members, submitted documents, minutes of meetings,
and correspondence) for a period of at least 3 years after completion of the trial and make
them available upon request from the regulatory authority(ies).
The IRB/IEC may be asked by investigators, sponsors, or regulatory authorities to provide
copies of its written procedures and membership lists.
4.
INVESTIGATOR 
4.1
Investigator's Qualifications and Agreements
4.1.1  The investigator(s) should be qualified by education, training, and
experience to assume responsibility for the proper conduct of the trial, should meet
all the qualifications specified by the applicable regulatory requirement(s), and
should provide evidence of such qualifications through up-to-date curriculum vitae
and/or other relevant documentation requested by the sponsor, the IRB/IEC,
and/or the regulatory authority(ies).
4.1.2  The investigator should be thoroughly familiar with the appropriate use of
the investigational product(s), as described in the protocol, in the current
Investigator's Brochure, in the product information, and in other information
sources provided by the sponsor.


14
4.1.3  The investigator should be aware of, and should comply with, GCP and the
applicable regulatory requirements.
4.1.4  The investigator/institution should permit monitoring and auditing by the
sponsor, and inspection by the appropriate regulatory authority(ies).
4.1.5  The investigator should maintain a list of appropriately qualified persons to
whom the investigator has delegated significant trial-related duties.
4.2
Adequate Resources
4.2.1  The investigator should be able to demonstrate (e.g., based on retrospective
data) a potential for recruiting the required number of suitable subjects within the
agreed recruitment period.
4.2.2  The investigator should have sufficient time to properly conduct and
complete the trial within the agreed trial period.
4.2.3  The investigator should have available an adequate number of qualified staff
and adequate facilities for the foreseen duration of the trial to conduct the trial
properly and safely.
4.2.4  The investigator should ensure that all persons assisting with the trial are
adequately informed about the protocol, the investigational product(s), and their
trial-related duties and functions.
4.3
Medical Care of Trial Subjects
4.3.1  A qualified physician (or dentist, when appropriate), who is an investigator
or a subinvestigator for the trial, should be responsible for all trial-related medical
(or dental) decisions. 
4.3.2  During and following a subject's participation in a  trial, the
investigator/institution should ensure that adequate medical care is provided to a
subject for any adverse events, including clinically significant laboratory values,
related to the trial. The investigator/institution should inform a subject when
medical care is needed for intercurrent illness(es) of which the investigator
becomes aware. 
4.3.3  It is recommended that the investigator inform the subject's primary
physician about the subject's participation in the trial if the subject has a primary
physician and if the subject agrees to the primary physician being informed.


15
4.3.4  Although a subject is not obliged to give his/her reason(s) for withdrawing
prematurely from a trial, the investigator should make a reasonable effort to
ascertain the reason(s), while fully respecting the subject's rights.
4.4
Communication with IRB/IEC
4.4.1  Before initiating a trial, the investigator/institution should have written and
dated approval/favorable opinion from the IRB/IEC for the trial protocol, written
informed consent form, consent form updates, subject recruitment procedures
(e.g., advertisements), and any other written information to be provided to
subjects. 
4.4.2  As part of the investigator's/institution’s written application to the IRB/IEC,
the investigator/institution should provide the IRB/IEC with a current copy of the
Investigator's Brochure.  If the Investigator's Brochure is updated during the trial,
the investigator/institution should supply a copy of the updated Investigator’s
Brochure to the IRB/IEC.
4.4.3  During the trial the investigator/institution should provide to the IRB/IEC all
documents subject to its review.  
4.5
Compliance with Protocol
4.5.1  The investigator/institution should conduct the trial in compliance with the
protocol agreed to by the sponsor and, if required, by the regulatory authority(ies),
and which was given approval/favorable opinion by the IRB/IEC.  The
investigator/institution and the sponsor should sign the protocol, or an alternative
contract, to confirm their agreement.
4.5.2  The investigator should not implement any deviation from, or changes of,
the protocol without agreement by the sponsor and prior review and documented
approval/favorable opinion from the IRB/IEC of an amendment, except where
necessary to eliminate an immediate hazard(s) to trial subjects, or when the
change(s)  involves only logistical or administrative aspects of the trial (e.g.,
change of monitor(s), change of telephone number(s)).
4.5.3  The investigator, or person designated by the investigator, should document
and explain any deviation from the approved protocol.
4.5.4  The investigator may implement a deviation from, or a change in, the
protocol to eliminate an immediate hazard(s) to trial subjects without prior
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16
 deviation or change, the reasons for it, and, if appropriate, the proposed protocol
amendment(s) should be submitted:
(a)  To the IRB/IEC for review and approval/favorable opinion;
(b)  To the sponsor for agreement and, if required; 
(c)  To the regulatory authority(ies).
4.6
Investigational Product(s)
4.6.1  Responsibility for investigational product(s) accountability at the trial site(s)
rests with the investigator/institution.
4.6.2  Where allowed/required, the investigator/institution may/should assign some
or all of the investigator's/institution’s duties for investigational product(s)
accountability at the trial site(s) to an appropriate pharmacist or another
appropriate individual who is under the supervision of the investigator/institution.
4.6.3  The investigator/institution and/or a pharmacist or other appropriate
individual, who is designated by the investigator/institution, should maintain
records of the product's delivery to the trial site, the inventory at the site, the use
by each subject, and the return to the sponsor or alternative disposition of unused
product(s).  These records should include dates, quantities, batch/serial numbers,
expiration dates (if applicable), and the unique code numbers assigned to the
investigational product(s) and trial subjects. Investigators should maintain records
that document adequately that the subjects were provided the doses specified by
the protocol and reconcile all investigational product(s) received from the sponsor.
4.6.4  The investigational product(s) should be stored as specified by the sponsor
(see sections 5.13.2 and 5.14.3) and in accordance with applicable regulatory
requirement(s).
4.6.5  The investigator should ensure that the investigational product(s) are used
only in accordance with the approved protocol.
4.6.6  The investigator, or a person designated by the investigator/institution,
should explain the correct use of the investigational product(s) to each subject and
should check, at intervals appropriate for the trial, that each subject is following
the instructions properly.
4.7
Randomization Procedures and Unblinding
The investigator should follow the trial's randomization procedures, if any, and should
ensure that the code is broken only in accordance with the protocol.  If the trial is blinded,


17
the investigator should promptly document and explain to the sponsor any premature
unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the
investigational product(s).
4.8
Informed Consent of Trial Subjects
4.8.1  In obtaining and documenting informed consent, the investigator should
comply with the applicable regulatory requirement(s), and should adhere to GCP
and to the ethical principles that have their origin in the Declaration of Helsinki. 
Prior to the beginning of the trial, the investigator should have the IRB/IEC's
written approval/favorable opinion of the written informed consent form and any
other written information to be provided to subjects.
4.8.2  The written informed consent form and any other written information to be
provided to subjects should be revised whenever important new information
becomes available that may be relevant to the subject’s consent.  Any revised
written informed consent form, and written information should receive the
IRB/IEC's approval/favorable opinion in advance of use.  The subject or the
subject’s legally acceptable representative should be informed in a timely manner if
new information becomes available that may be relevant to the subject’s
willingness to continue participation in the trial.  The communication of this
information should be documented.
4.8.3  Neither the investigator, nor the trial staff, should coerce or unduly influence
a subject to participate or to continue to participate in a trial.
4.8.4  None of the oral and written information concerning the trial, including the
written informed consent form, should contain any language that causes the subject
or the subject's legally acceptable representative to waive or to appear to waive
any legal rights, or that releases or appears to release the investigator, the
institution, the sponsor, or their agents from liability for negligence.
4.8.5  The investigator, or a person designated by the investigator, should fully
inform the subject or, if the subject is unable to provide informed consent, the
subject's legally acceptable representative, of all pertinent aspects of the trial
including the written information given approval/favorable opinion by the
IRB/IEC.
4.8.6  The language used in the oral and written information about the trial,
including the written informed consent form, should be as nontechnical as practical
and should be understandable to the subject or the subject's legally acceptable
representative and the impartial witness, where applicable. 


18
4.8.7  Before informed consent may be obtained, the investigator, or a person
designated by the investigator, should provide the subject or the subject's legally
acceptable representative ample time and opportunity to inquire about details of
the trial and to decide whether or not to participate in the trial.  All questions
about the trial should be answered to the satisfaction of the subject or the subject's
legally acceptable representative.
4.8.8  Prior to a subject’s participation in the trial, the written informed consent
form should be signed and personally dated by the subject or by the subject's
legally acceptable representative, and by the person who conducted the informed
consent discussion. 
4.8.9  If a subject is unable to read or if a legally acceptable representative is
unable to read, an impartial witness should be present during the entire informed
consent discussion.  After the written informed consent form and any other written
information to be provided to subjects is read and explained to the subject or the
subject’s legally acceptable representative, and after the subject or the subject’s
legally acceptable representative has orally consented to the subject’s participation
in the trial, and, if capable of doing so, has signed and personally dated the
informed consent form, the witness should sign and personally date the consent
form.  By signing the consent form, the witness attests that the information in the
consent form and any other written information was accurately explained to, and
apparently understood by, the subject or the subject's legally acceptable
representative, and that informed consent was freely given by the subject or the
subject’s legally acceptable representative.
4.8.10  Both the informed consent discussion and the written informed consent
form and any other written information to be provided to subjects should include
explanations of the following:
(a)  That the trial involves research.
(b)  The purpose of the trial.
(c)  The trial treatment(s) and the probability for random assignment to
each treatment.
(d)  The trial procedures to be followed, including all invasive procedures.
(e)  The subject's responsibilities.
(f)  Those aspects of the trial that are experimental.


19
(g)  The reasonably foreseeable risks or inconveniences to the subject and,
when applicable, to an embryo, fetus, or nursing infant.
(h)  The reasonably expected benefits.  When there is no intended clinical
benefit to the subject, the subject should be made aware of this. 
(i)  The alternative procedure(s) or course(s) of treatment that may be
available to the subject, and their important potential benefits and risks. 
(j)  The compensation and/or treatment available to the subject in the event
of trial-related injury. 
(k)  The anticipated prorated payment, if any, to the subject for
participating in the trial.
(l)  The anticipated expenses, if any, to the subject for participating in the
trial.
(m)  That the subject's participation in the trial is voluntary and that the
subject may refuse to participate or withdraw from the trial, at any time,
without penalty or loss of  benefits to which the subject is otherwise
entitled. 
(n)  That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory
authority(ies) will be granted direct access to the subject's original medical
records for verification of clinical trial procedures and/or data, without
violating the confidentiality of the subject, to the extent permitted by the
applicable laws and regulations and that, by signing a written informed
consent form, the subject or the subject's legally acceptable representative
is authorizing such access.
(o)  That records identifying the subject will be kept confidential and, to the
extent permitted by the applicable laws and/or regulations, will not be made
publicly available.  If the results of the trial are published, the subject’s
identity will remain confidential. 
(p)  That the subject or the subject's legally acceptable representative will
be informed in a timely manner if information becomes available that may
be relevant to the subject's willingness to continue participation in the trial. 
(q)  The person(s) to contact for further information regarding the trial and
the rights of trial subjects, and whom to contact in the event of trial-related
injury. 


20
(r)  The foreseeable circumstances and/or reasons under which the subject's
participation in the trial may be terminated. 
(s)  The expected duration of the subject's participation in the trial.
(t)  The approximate number of subjects involved in the trial. 
4.8.11  Prior to participation in the trial, the subject or the subject's legally
acceptable representative should receive a copy of the signed and dated written
informed consent form and any other written information provided to the subjects. 
During a subject’s participation in the trial, the subject or the subject’s legally
acceptable representative should receive a copy of the signed and dated consent
form updates and a copy of any amendments to the written information provided
to subjects.
4.8.12  When a clinical trial (therapeutic or nontherapeutic) includes subjects who
can only be enrolled in the trial with the consent of the subject’s legally acceptable
representative (e.g., minors, or patients with severe dementia), the subject should
be informed about the trial to the extent compatible with the subject’s
understanding and, if capable, the subject should assent, sign and personally date
the written informed consent.
4.8.13  Except as described in 4.8.14, a nontherapeutic trial (i.e., a trial in which
there is no anticipated direct clinical benefit to the subject) should be conducted in
subjects who personally give consent and who sign and date the written informed
consent form.
4.8.14  Nontherapeutic trials may be conducted in subjects with consent of a
legally acceptable representative provided the following conditions are fulfilled:
(a)  The objectives of the trial cannot be met by means of a trial in subjects
who can give informed consent personally.
(b)  The foreseeable risks to the subjects are low.
(c)  The negative impact on the subject’s well-being is minimized and low.
(d)  The trial is not prohibited by law.
(e)  The approval/favorable opinion of the IRB/IEC is expressly sought on
the inclusion of such subjects, and the written approval/favorable opinion
covers this aspect. 


21
Such trials, unless an exception is justified, should be conducted in patients having
a disease or condition for which the investigational product is intended.  Subjects
in these trials should be particularly closely monitored and should be withdrawn if
they appear to be unduly distressed.
4.8.15  In emergency situations, when prior consent of the subject is not possible,
the consent of the subject's legally acceptable representative, if present, should be
requested.  When prior consent of the subject is not possible, and the subject’s
legally acceptable representative is not available, enrollment of the subject should
require measures described in the protocol and/or elsewhere, with documented
approval/favorable opinion by the IRB/IEC, to protect the rights, safety, and well-
being of the subject and to ensure compliance with applicable regulatory
requirements.  The subject or the subject's legally acceptable representative should
be informed about the trial as soon as possible and consent to continue and other
consent as appropriate (see section 4.8.10) should be requested.
4.9
Records and Reports
4.9.1  The investigator should ensure the accuracy, completeness, legibility, and
timeliness of the data reported to the sponsor in the CRFs and in all required
reports.
4.9.2  Data reported on the CRF, which are derived from source documents,
should be consistent with the source documents or the discrepancies should be
explained.
4.9.3  Any change or correction to a CRF should be dated, initialed, and explained
(if necessary) and should not obscure the original entry (i.e., an audit trail should
be maintained); this applies to both written and electronic changes or corrections
(see section 5.18.4(n)).  Sponsors should provide guidance to investigators and/or
the investigators' designated representatives on making such corrections.  Sponsors
should have written procedures to assure that changes or corrections in CRFs
made by sponsor's designated representatives are documented, are necessary, and
are endorsed by the investigator.  The investigator should retain records of the
changes and corrections.
4.9.4  The investigator/institution should maintain the trial documents as specified
in Essential Documents for the Conduct of a Clinical Trial (see section 8.) and as
required by the applicable regulatory requirement(s).  The investigator/institution
should take measures to prevent accidental or premature destruction of these
documents.


22
4.9.5  Essential documents should be retained until at least 2 years after the last
approval of a marketing application in an ICH region and until there are no
pending or contemplated marketing applications in an ICH region or at least 2
years have elapsed since the formal discontinuation of clinical development of the
investigational product.  These documents should be retained for a longer period,
however, if required by the applicable regulatory requirements or by an agreement
with the sponsor.  It is the responsibility of the sponsor to inform the
investigator/institution as to when these documents no longer need to be retained
(see section 5.5.12).
4.9.6  The financial aspects of the trial should be documented in an agreement
between the sponsor and the investigator/institution.
4.9.7  Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
investigator/institution should make available for direct access all requested trial-
related records. 
4.10
Progress Reports
4.10.1  Where required by the applicable regulatory requirements, the investigator
should submit written summaries of the trial’s status to the institution.  The
investigator/institution should submit written summaries of the status of the trial to
the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.
4.10.2  The investigator should promptly provide written reports to the sponsor,
the IRB/IEC (see section 3.3.8), and, where required by the applicable regulatory
requirements, the institution on any changes significantly affecting the conduct of
the trial, and/or increasing the risk to subjects.
4.11
Safety Reporting
4.11.1  All serious adverse events (SAEs) should be reported immediately to the
sponsor except for those SAEs that the protocol or other document (e.g.,
Investigator's Brochure) identifies as not needing immediate reporting.  The
immediate reports should be followed promptly by detailed, written reports.  The
immediate and follow-up reports should identify subjects by unique code numbers
assigned to the trial subjects rather than by  the subjects' names, personal
identification numbers, and/or addresses.  The investigator should also comply
with the applicable regulatory requirement(s) related to the reporting of
unexpected serious adverse drug reactions to the regulatory authority(ies) and the
IRB/IEC.


23
4.11.2  Adverse events and/or laboratory abnormalities identified in the protocol as
critical to safety evaluations should be reported to the sponsor according to the
reporting requirements and within the time periods specified by the sponsor in the
protocol.
4.11.3  For reported deaths, the investigator should supply the sponsor and the
IRB/IEC with any additional requested information (e.g., autopsy reports and
terminal medical reports).
4.12
Premature Termination or Suspension of a Trial
If the trial is terminated prematurely or suspended for any reason, the
investigator/institution should promptly inform the trial subjects, should assure appropriate
therapy and follow-up for the subjects, and, where required by the applicable regulatory
requirement(s), should inform the regulatory authority(ies).  In addition:
4.12.1  If the investigator terminates or suspends a trial without prior agreement of
the sponsor, the investigator should inform the institution, where required by the
applicable regulatory requirements, and the investigator/institution should
promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and
the IRB/IEC a detailed written explanation of the termination or suspension.
4.12.2  If the sponsor terminates or suspends a trial (see section 5.21), the
investigator should promptly inform the institution, where required by the
applicable regulatory requirements, and the investigator/institution should
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written
explanation of the termination or suspension.
4.12.3  If the IRB/IEC terminates or suspends its approval/favorable opinion of a
trial (see sections 3.1.2 and 3.3.9), the investigator should inform the institution,
where required by the applicable regulatory requirements, and the
investigator/institution should promptly notify the sponsor and provide the sponsor
with a detailed written explanation of the termination or suspension.
4.13
Final Report(s) by Investigator/Institution
Upon completion of the trial, the investigator should, where required by the applicable
regulatory requirements, inform the institution, and the investigator/institution should
provide the sponsor with all required reports, the IRB/IEC with a summary of the trial’s
outcome, and the regulatory authority(ies) with any report(s) they require of the
investigator/institution.


CONFIDENTIAL AND PROPRIETARY INFORMATION OF AVANIR PHARMACEUTICALS, INC. 
Protocol 15-AVP-786-202 
Version 5.0 
15-AVP-786-202-Amendment 04 
Version 5.0 
Appendix 14: 
World Medical Association Declaration Helsinki 


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World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
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13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
Clinical Review & Education Special Communication
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
JAMA
November 27, 2013
Volume 310, Number 20
jama.com
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CONFIDENTIAL AND PROPRIETARY INFORMATION OF AVANIR PHARMACEUTICALS, INC. 
Protocol 15-AVP-786-202 
Version 5.0 
15-AVP-786-202-Amendment 04 
Version 5.0 


CONFIDENTIAL AND PROPRIETARY INFORMATION OF AVANIR PHARMACEUTICALS, INC. 
Protocol 15-AVP-786-202 
Version 5.0 
15-AVP-786-202-Amendment 04 
 
 
 
 
Version 5.0 
 

SAP_000.pdf: 
NCT Number: NCT02477670
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Statistical Analysis Plan: 15-A VP-786-202 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ................................................................................................... 2 
LIST OF TABLES ..................................................................................................................... 5 
LIST OF FIGURES ................................................................................................................... 5 
LIST OF APPENDICES ............................................................................................................ 5 
2 
SIGNATURE PAGE ......................................................................................................... 6 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................... 7 
4 
INTRODUCTION ............................................................................................................. 9 
5 
TRIAL OBJECTIVES ....................................................................................................... 9 
5.1 
Primary Objectives ................................................................................................... 9 
5.2 
Secondary Objectives ............................................................................................... 9 
6 
STUDY DESIGN CONSIDERATIONS ........................................................................... 9 
6.1 
Study Design and Population ................................................................................... 9 
6.2 
Study Drug Administration .................................................................................... 11 
................................................................................................... 12 
7 
STUDY ENDPOINTS ..................................................................................................... 12 
7 .1 
Scales and Questio1maires ...................................................................................... 12 
7.1.l 
16-Item and 4-Item Negative Symptom Assessments (NSA-16, NSA-4) .. .12 
7.1.2 
Positive and Negative Syndrome Scale (PANSS) ....................................... 13 
7.1.3 
Clinical Global Impression (CGI) Scales .................................................... 14 
7.1.3.l 
Clinical Global Impression-Severity (CGI-S) ................................ .15 
7.1.3.2 
Clinical Global Impression :-- Change (CGI-C) ................................. 15 
7 .1.3 .3 
Patient Global Impression - Change (PGIC) .................................... .15 
7 .1.4 
Calgary Depression Scale for Schizophrenia (CDSS) ................................. 16 
7.1.5 
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia (MA TRI CS) Consensus Cognitive Battery (MCCB) .......... 16 
7 .1. 6 
Effort Expenditure for Reward Task (EEfR T) ............................................. 16 
.......................................................... 17 
7.1.8 
Mini International Neuropsychiatric Interview (M.I.N.I.) Version 6.0.0 .... 17 
7.1.9 
Columbia Suicide Severity Rating Scale (C-SSRS) .................................... 17 
7. 1.10 
Simpson Angus Scale for Extrapyramidal Symptoms (SAS) ...................... 18 
7 .1.11 
Barnes Akathisia Scale (BAS) ..................................................................... 18 
7.1.12 
Abnormal Involuntary Movements Scale (AIMS) ...................................... 18 
7 .2 
Efficacy Endpoints ................................................................................................. 18 
7 .3 
Safety Endpoints .................................................................................................... 19 
7.4 
Pharmacokinetic, 
 Parameters ....................................... 19 
8 
ANALYSIS POPULATIONS ......................................................................................... 19 
8.1 
Modified Intent-to-Treat (mITT) Population ......................................................... 20 
.............................................................................. 20 
Confidential 
Page 2 of52 


Statistical Analysis Plan: 15-A VP-786-202 
....................................................................... 20 
....................................................................... 21 
8.3 
Safety Population ................................................................................................... 21 
................................... 21 
................................... 21 
................................... 21 
................................... 21 
9 
OVERALL STATISTICAL CONSIDERATIONS ......................................................... 22 
9 .1 
Definition of Baseline ............................................................................................ 22 
9.2 
Definition of End ofTreatment.. ............................................................................ 22 
9.3 
Change from Baseline ............................................................................................ 22 
9.4 
Visit Windows ....................................................................................................... 22 
9.5 
Handling of Missing Data ...................................................................................... 24 
9.6 
Treatment Misallocations ....................................................................................... 24 
9.7 
Summary Statistics ................................................................................................. 25 
9.8 
Data Listings .......................................................................................................... 25 
9.9 
Graphical Displays ................................................................................................. 25 
9 .10 
Hypothesis Testing ................................................................................................. 25 
9 .11 
Multiplicity of Secondary Endpoints ..................................................................... 25 
10 
EFFICACY STATISTICAL ANALYSIS METHODS ................................................... 25 
10.1 
Primary Efficacy: SPCD MMRM (Mixed-Model Repeated Measures) ............... 25 
........ 26 
........ 26 
........ 27 
........ 28 
10.3 
Secondary Efficacy Analysis ................................................................................. 28 
10.3.1 
Secondary SPCD MMRM and SPCD OLS ANCOVA ............................... 29 
10.3.2 
P ANSS Response Analysis .......................................................................... 29 
...... .29 
...... 30 
...... 30 
...... 30 
...... 30 
...... 30 
...... 31 
...... 31 
...... 31 
Confidential 
Page 3 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
.. 32 
... 32 
11 
SAFETY STATISTICAL ANALYSIS METHODS ....................................................... 33 
11 .1 
Adverse Events ...................................................................................................... 34 
11 .2 
Clinical Laboratory Assessments ........................................................................... 36 
11.3 
ECGs ...................................................................................................................... 37 
11 .4 
Vital Signs .............................................................................................................. 38 
11.5 
Physical and Neurological Exams ......................................................................... 39 
11 .6 
C-SSRS .................................................................................................................. 39 
11. 7 
Simpson Angus Scale for Extrapyramidal Symptoms (SAS) ............................... .40 
11 .8 
Barnes Akathisia Scale (BAS) .............................................................................. .40 
11.9 
Abnonnal Involuntary Movement Scale (AIMS) ................................................. .40 
12 
ADDITIONAL STATISTICAL ANALYSIS METHODS ............................................ .41 
12.1 
Patient Disposition ................................................................................................ .41 
12.2 
Demographics and Baseline Characteristics ......................................................... .41 
12.3 
Medical History and Disease Characteristics ........................................................ 42 
12.4 
Exposure and Treatment Compliance ................................................................... .42 
12.5 
Prior and Concomitant Medications ..................................................................... .43 
12.6 
Analysis of Phaimacokinetics and Pharmacodynamics ........................................ .43 
13 
ADDITIONAL STATISTICAL CONSIDERATIONS ................................................... 44 
13.1 
Data Safety Monitoring Board (DSMB) ............................................................... .44 
13.2 
Changes from Protocol ......................................................................................... .44 
14 
REFERENCES ................................................................................................................ 45 
15 
APPENDICES ................................................................................................................. 46 
Confidential 
Page 4 of52 


Statistical Analysis Plan: 15-A VP-786-202 
LIST OF TABLES 
Table 1. Overview of Study Duration ........................................................................................ 9 
Table 2. Visit Windows for Assessments Done at Baseline and Weeks 2, 3, 6, 8, 9, 12 ........ 23 
Table 3. Visit Windows for Assessments Done at Baseline and Weeks 3, 6, 9, and 12 ........ .23 
Table 4. Visit Windows for Assessments Done at Baseline, Week 6, and Week 12 Only ..... 23 
Table 5. Lab PCS Criteria ........................................................................................................ 37 
Table 6. ECG PCS Criteria ...................................................................................................... 38 
Table 7. Vital Sign PCS Criteria .............................................................................................. 39 
LIST OF FIGURES 
Figure 1. Study Schematic (With Treatment Segments) ....................................................... .11 
LIST OF APPENDICES 
Appendix 1 Schedule of Assessments and Procedures ........................................................... .47 
................................................... .48 
Appendix 3 Prior and Concomitant Medication Start Date Imputation .................................. 50 
 ....... 51 
Appendix 5 List of Selective serotonin-norepinepherine reuptake inhibitors (SNRis) ........... 52 
Confidential 
Page 5 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
2 SIGNATURE PAGE 
Study Title: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Assess the Efficacy, Safety, and Tolerability 
of A VP-786 (Deuterium Modified Dextromethorphan 
Hydrobromide/Quinidine Sulfate) as an Adjunctive Therapy in 
Patients with Residual Schizophrenia 
Study Number: 
15-A VP-786-202 
Prepared by: 
Approved by
Approved by
Approved by
Approved by:
Approved by:
Confidential 
Page 6 of 52 
8/15/2017 
8/15/2017 
8/15/2017 
8/15/2017 
8/15/2017 
8/15/2017 


Statistical Analysis Plan: 15-A VP-786-202 
3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AA 
AE 
AIMS 
ALT/SGPT 
ANCOVA 
AST/SGOT 
AUC 
AVP-786 
BAS 
BID 
BP 
bpm 
BUN 
Cm ax 
CDSS 
CFBL 
CGI-C 
CGI-S 
CK 
C-SSRS 
 
d6-DM 
DM 
DSMB 
DSM-IV-TR 
ECG 
eCRF 
EEtRT 
FDA 
GGT 
HbAlc 
HR 
ICF 
ITT 
LDH 
LOCF 
Confidential 
Apathy avolition 
Adverse event 
Abnormal Involuntary Movements Scale 
Alanine aminotransferase/serum glutamic-pyruvic transaminase 
Analysis of covariance 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
Area under the concentration-time curve 
Deuterated [ d6]-dextromethorphan hydro bromide and quinidine sulfate 
combination 
Barnes Akathisia Scale 
Twice-daily 
Blood pressure 
Beats per minute 
Blood urea nitrogen 
Maximum plasma concentration 
Calgary Depression Scale for Schizophrenia 
Change from Baseline 
Clinical Global Impression of Change 
Clinical Global Impression of Severity of Illness 
Creatine kinase 
Columbia Suicide Severity Rating Scale 
 Subject Database 
Deuterated ( d6)-dextromethorphan hydro bromide 
Dextromethorphan hydrobromide 
Data and Safety Monitoring Board 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text 
Revision 
Electrocardiogram 
Electronic case report form 
Effort Expenditure for Reward Task 
US Food and Drug Administration 
Gamma-gl utamyl transferase 
Glycosylated hemoglobin 
Heart rate 
Informed Consent Form 
Intent-to-Treat 
Lactate dehydrogenase 
Last observation carried forward 
Page 7 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
M.l.N.I. 
MATRICS 
MCCB 
MedDRA 
mg 
mITT 
MMRM 
NSA-16 
NSA-4 
OLS 
PANSS 
PCS 
PD 
PGIC 
pH 
PK 
pp 
PT 
Q 
QD 
QRS 
QT 
QTc 
QTcF 
SAE 
SAP 
SAS 
SAS® 
SGA 
soc 
SNRI 
SPCD 
SSRI 
SUR 
TEAE 
TFLs 
ULN 
us 
WHO 
Confidential 
Mini International Neuropsychiatric Interview 
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia 
MATRICS Consensus Cognitive Battery 
Medical Dictionary for Regulatory Activities 
Milligram( s) 
Modified Intent-to-Treat 
Mixed-effects model for repeated measures 
16-Item Negative Symptom Assessment 
4-Item Negative Symptom Assessment 
Ordinary least squares 
Positive and Negative Syndrome Scale 
Potentially clinically significant 
Pharmacod ynamic( s) 
Patient Global Impression of Change 
Potential hydrogen 
Pharmacokinetic( s) 
Per-protocol 
Preferred Term 
Quinidine (sulfate) 
Once daily 
The Q-R-S complex from an ECG tracing 
QT interval from an ECG tracing 
QT interval corrected for heart rate 
QT interval corrected for heart rate using the Fridericia's fo1mula 
Serious adverse event 
Statistical analysis plan 
Simpson Angus Scale for Extrapyramidal Symptoms 
Statistical Analysis Software 
Second generation antipsychotic 
System Organ Class 
Selective serotonin-norepinephrine reuptake inhibitor 
Sequential parallel comparison design 
Selective serotonin reuptake inhibitor 
Seemingly unrelated regression 
Treatment-emergent adverse event 
Tables, figures, and listings 
Upper limit of normal 
United States of America 
World Health Organization 
Page 8 of 52 


Statistical Analysis Plan: 15-AVP-786-202 
4 INTRODUCTION 
This document provides a detailed description of the statistical methods and procedures to be 
implemented during the analysis of Avanir Pharmaceuticals Incorporated Protocol 15-AVP-
786-202 (Amendment 4, Version 5), dated 25 January 2016. 
5 TRIAL OBJECTIVES 
The objectives of this 12-week study are to evaluate the efficacy, safety, and tolerability of 
A VP-786, a combination of deuterated-dextromethorphan hydro bromide ( d6-DM) and 
quinidine sulfate (Q), as an adjunctive therapy compared with placebo in patients with 
residual schizophrenia on negative and positive symptoms and cognitive function. 
5.1 
Primary Objectives 
The primary study objective is to evaluate the efficacy of A VP-786 compared to placebo for 
the treatment of negative symptoms associated with schizophrenia, as measured by the 16-
item Negative Symptom Assessment (NSA-16) total score. 
5.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the efficacy, safety, and tolerability of 
A VP-786 compared to placebo in patients with residual schizophrenia. 
• 
Clinical Efficacy will be measured by the Positive and Negative Syndrome Scale 
(PANSS) total score and PANSS subscales; NSA-16 factor domains, global score, 
individual items, and NSA-4; proportion of patients with a reduction of20% or 
greater in the PANSS total score; MCCB composite score, CGI-S, CGI-C, and PGIC 
scores; CDSS; and EEfRT. 
• 
Safety and tolerability will be measured by reported AEs, SAEs, physical 
examinations, vital signs, weight, pregnancy tests, clinical laboratory assessments, 
12-lead ECGs, as well as C-SSRS, AIMS, BAS, and SAS scales. 
6 STUDY DESIGN CONSIDERATIONS 
6.1 
Study Design and Population 
This is a prospective, multicenter, randomized, double-blind, placebo-controlled study with a 
duration of 12 weeks, consisting of 2 consecutive double-blind treatment stages, each 6 
weeks in duration (Stage 1 and Stage 2). The study utilizes a Sequential Parallel Comparison 
Design (SPCD). 
Table 1. Overview of Study Duration 
Screening 
Stage I 
Stage 2 
Telephone Follow-Up 
Duration in Days 
Day-28 to -7 
Day 1to42 
Day 43 to 85 
Day 86 to 90 
Confidential 
Page 9 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
Approximately 120 patients will participate in the study at roughly 15 research centers in the 
United States. Eligible patients for this study must be adult outpatients (between 18 and 60 
years of age) who are diagnosed with schizophrenia, are clinically stable, in a residual (non-
acute) phase of illness, and will have been treated with a second generation antipsychotic 
(SGA) agent for at least 3 months (90 days) and on a stable dose for 1 month (30 days) prior 
to the Screening Visit. The diagnosis of residual schizophrenia will be based on the 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-
TR). 
Initial randomization will occur at baseline and will mark the start of Stage 1. Patients will 
be randomized in a 
 ratio (A VP-786 to placebo). 
Patients who have completed Stage 1 are eligible to participate in Stage 2 of the study, which 
is also 6 weeks long. Stage 2 starts at Week 7 and will continue to the end of Week 12. 
Patients who received placebo in Stage 1 will be further stratified into 2 subgroups 
("responders" and "non-responders") based on their response to the 
 
 from the Baseline total score 
constitutes a response. Each subgroup will be re-randomized to receive A VP-786 or placebo 
in a 
 ratio. Patients who received A VP-786 in Stage 1 will continue to receive A VP-786 
for the entire 6-week duration of Stage 2. 
Clinic visits will occur at Screening, BaselineNisit 1 (Day 1 ), Week 2Nisit 2 (Day 15), 
Week 3Nisit 3 (Day 22), Week 6Nisit 4 (Day 43), Week 8Nisit 5 (Day 57), Week 9Nisit 6 
(Day 64), and Week 12/Visit 7/Early Termination (Day 85). A schematic of the study along 
with the visit schedule and treatment segments is shown in Figure 1. The letters for each 
treatment segment are described below and will be used throughout the Statistical Analysis 
Plan (SAP) for clarity: 
• 
A: A= Al + A2, where Al and A2 are the Stage 1 data for patients who are 
randomized to Placebo/Placebo and Placebo/AVP-786, respectively. 
• 
B: Stage 1 data for patients randomized to A VP-786 in Stage 1 
• 
C: Stage 2 data for patients who were placebo 'responders' in Stage 1 and 
re-randomized to placebo in Stage 2 
• 
D: Stage 2 data for patients who were placebo 'responders' in Stage 1 and 
re-randomized to A VP-786 in Stage 2 
• 
E: Stage 2 data for patients who were placebo 'non-responders' in Stage 1 and 
re-randomized to placebo in Stage 2 
• 
F: Stage 2 data for patients who were placebo 'non-responders' in Stage 1 and 
re-randomized to AVP-786 in Stage 2 
• 
G: Stage 2 A VP-786 data for patients randomized to A VP-786 in Stage 1. 
Confidential 
Page 10 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
Figure 1. 
Study Schematic (With Treatment Segments) 
Protocol 15-AVP-786-202 (Schizophrenia Study) 
Stratification by Site 
Stratification based on Treatment Response 
Randomization Baseline/Visit 1(Day1) 
Re-Randomization Visit 4 (Day 43)' 
Placebo 
c 
~-""l 
D 
.......... 
AVP-786 
M
34/4.9 
34/4.9 
34/4.9 
34/4.9 
E Placebo 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
Placebo 
A(= Al+A2)** 
Placebo 
E 
,00~'"'"""1 
F 
Screening 
AVP-786 
M
34/4.9 
34/4.9 
34/4.9 
34/4.9 
E Placebo 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
B 
G 
AVP-786 
AVP-786 
M
34/4.9 
34/4.9 
34/4.9 
34/4.9 
M 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
E Placebo 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
E 34/4.9 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
34/4.9 
Period 
Screening 
Stage 1 
Stage 2 
Visit 
Screening 
Baseline I 
I 
V3 
I 
I 
I V4' 
I 
I 
V6 
I 
I 
I 
V7 
Day 
-28 
I 
-7 
1 
I 
I 
22 
I 
I 
I 
43' 
I 
I 
64 
I 
I 
I 
85 
Week 
Week -4 
Week 1 I Week 2 I Week 3 I Week 4 I Week 5 I Week 6 
Week 7 I Week 8 I Week 9 I Week 10 I Week 11 I Week 12 
Study medication (active or placebo) will be administered as 1 capsule in the morning and 1 capsule in the evening approximately 12 hours apart. 
M: 
Morning Dose (in mg d6-DM/mg QJ 
E: 
Evening Dose (in mg d6-DM/mg Q) 
Visit 4 (Day 43) stratification is based on treatment response criteria followed by Re-Randomization 
. 
Al, A2 are the Stage 1 data for patients who are randomized to Placebo/Placebo and Placebo/AVP-786, respectively. 
6.2 
Study Drug Administration 
Study medication will be administered orally BID throughout the study. 
Patients randomized to receive active drug will start with 
 mg of d6-DM and 
 mg of Q 
(AVP-786 
) once a day (QD) for the first 7 days of the study in the morning and 
matching placebo in the evening. Starting on Day 8, these patients will receive A VP-786 
 BID until their next scheduled visit and starting at Visit 2 (Day 15) their dose will be 
escalated to A VP-786 34/4.9 BID for the duration of the study. 
Patients randomized to receive placebo in Stage 1 will take placebo BID for the entire stage. 
Patients who are re-randomized to placebo will continue to receive placebo BID for the entire 
6-week duration of Stage 2. 
Patients who are re-randomized to A VP-786 at the beginning of Stage 2 will receive 
A VP-786 in the same dose escalating manner as patients in Stage 1. 
Confidential 
Page 11 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
7 STUDY ENDPOINTS 
7.1 
Scales and Questionnaires 
7.1.1 
16-Item and 4-Item Negative Symptom Assessments (NSA-16, NSA-4) 
The NSA-16 total score is the primary efficacy measure used in this study, and measures the 
presence, severity, and range of negative symptoms associated with schizophrenia. The 
NSA-16 is performed at Screening, BaselineNisit 1 (Day 1), Visit 3 (Day 22), Visit 4 (Day 
43), Visit 6 (Day 64), and Visit 7/Early Termination (Day 85). 
The NSA-16 consists of 16 items, and uses a 5-factor model to describe negative symptoms: 
Factor Domain 
Communication 
Emotion/ Affect 
Social Involvement 
Motivation 
Retardation 
Total 
NSA-16 Item Numbers 
1, 2, 3, 4 
5,6, 7 
8, 9, 10 
11, 12, 13, 14 
15, 16 
1-16 
Score Range 
4-24 
3-18 
3-18 
4-24 
3 -18 
16-96 
Each item is rated on a 6-point Likert scale from 1 to 6, with detailed descriptions of anchors 
at each point on the scale. The severity scores can be interpreted as follows: 
1 =The behavior being assessed is not reduced or absent as compared to a healthy young 
human. 
2 =The behavior being assessed is minimally reduced, significance is questionable. 
3 =The behavior being assessed is mildly reduced; it might only be noted as reduced by a 
trained rater, but he/she notes a definite reduction. 
4 =The behavior being assessed is moderately reduced; the reduction should be obvious 
to an untrained rater. 
Confidential 
Page 12 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
5 =The behavior being rated is markedly reduced; this behavior is easily observable and 
definitely interferes with the subject's functioning. 
6 =The behavior being assessed is severely reduced or entirely absent; it is glaring and 
markedly interferes with functioning. 
Furthermore, each item admits a score of 9 ifthe item is not ratable. The NSA-16 total score 
is defined as the sum of all 16 items excluding any items receiving a score of 9. If more than 
3 items are not ratable, the total score cannot be calculated and will be regarded as missing; 
otherwise, the total score will be calculated as 16 times the arithmetic mean of the scores of 
all ratable items, rounded to the nearest tenth. Therefore, the minimum score is 16 and the 
maximum score is 96, with a higher score indicating greater clinical severity of symptoms. 
Additionally, two global ratings are included: a global negative symptoms rating, which is 
scored on the basis of the overall impression of negative symptoms in the patient; and a 
global level of functioning, which represents the clinician's overall assessment of the 
patient's level of functioning, relative to a healthy young adult. Both are scored on the 
following scale: 
1 =No evidence of this symptom/impairment 
2 =Minimal evidence of this symptom/impairment 
3 =Mild evidence of this symptom/impairment 
4 =Moderate evidence of this symptom/impairment, apparent to the casual observer 
5 =Marked evidence of this symptom/impairment, readily apparent to the casual observer 
6 =Severe symptom/impairment, not only obvious but has marked impact on functioning 
7 =Extremely severe symptom/impairment that is incapacitating for the subject. 
The NSA-4 is a subset of the NSA-16, using the following items: (1) restricted speech 
quantity; (2) emotion: reduced range; (3) reduced social drive; (4) reduced interests. 
Therefore, the NSA-4 total score ranges from 4 to 24. 
In addition to the NSA-16 total score as the primary efficacy endpoint, the NSA-16 
individual factor domain scores, global negative symptoms/functioning rating, individual 
item scores, and NSA-4 total score are secondary efficacy endpoints. For each factor 
domain, scores will be calculated only if all items in that domain are rated; otherwise, it will 
be regarded as missing. 
7.1.2 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is a 30-item clinical scale to assess positive and negative symptoms of 
schizophrenia, and is performed at Screening, BaselineNisit 1 (Day 1 ), Visit 3 (Day 22), 
Visit 4 (Day 43), Visit 6 (Day 64), and Visit 7/Early Termination (Day 85). 
Each item is rated on the following scale: 
1 =Absent. 
Confidential 
Page 13 of 52 


Statistical Analysis Plan: 15-A VP-786-202 
2 =Minimal: questionable or subtle or suspected pathology, or may allude to the extreme 
end of the normal range. 
3 =Mild: presence is clearly established but not pronounced, and interferes little in day-
to-day functioning. 
4 =Moderate: characterizes a symptom which, though representing a serious problem, 
either occurs only occasionally or intrudes on daily life only to a moderate extent. 
5 =Moderate to Severe: indicates marked manifestations that distinct impact on one's 
functioning but are not all-consuming and usually can be contained at will. 
6 =Severe: represents gross pathology that is present very frequently, proves highly 
disruptive to one's life, and often calls for direct supervision. 
7 =Extremely Severe: refers to the most serious level of psychopathology, whereby the 
manifestations drastically interfere in most or all major life functions, typically 
necessitating close supervision and assistance in many areas. 
Therefore, the P ANSS total score range is 30 to 210. Items can be grouped into the 
following subscales with the corresponding score ranges: 
Subscale 
Negative Subscale 
Positive Subscale 
General Psychopathology Subscale 
Prosocial Factors 
Marder Negative Factors 
Excitement Component 
Item Numbers 
Nl-N7 
Pl -P7 
Gl-G16 
G16, N2, N4, N7, P3, P6 
NI -N4, N6, G7, G16 
P4, P7, G4, G8, G14 
Score Range 
7-49 
7-49 
16-112 
6-42 
7-49 
5-35 
The P ANSS total score (N 1 - N7, P 1 - P7, G 1 - G 16), and the P ANSS subscales (positive, 
negative, general psychopathology, prosocial factors, Marder negative factors, excitement 
component) are secondary efficacy endpoints. 
Additionally, the proportion of patients with a reduction of 20% or greater in the PANSS 
total score will be calculated, and is a secondary efficacy endpoint. 
7.1.3 
Clinical Global Impression (CGI) Scales 
The CGI was developed to provide a brief, stand-alone assessment of the clinician's view of 
the patient's global functioning prior to and after initiating a study medication. The CGI 
provides an overall clinician-determined summary measure that takes into account all 
available information, including knowledge of the patient's history, psychosocial 
circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability 
to function. The following CGI scores are secondary efficacy endpoints, and each is rated on 
a scale of 1 to 7, with a score of 0 indicating no assessment was performed. 
Confidential 
Page 14 of52 


Statistical Analysis Plan: 15-A VP-786-202 
7.1.3.l 
Clinical Global Impression - Severity (CGl-S) 
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient's 
illness at the time of assessment, relative to the clinician's past experience with patients with 
the same diagnosis. Ratings range on the following scale: 
0 =Not assessed 
1 =Normal, not at all ill 
2 = Borderline ill 
3 =Mildly ill 
4 =Moderately ill 
5 =Markedly ill 
6 =Severely ill 
7 =Among the most extremely ill patients. 
The CGI-S will be performed at BaselineNisit 1 (Day 1), Visit 4 (Day 43), and Visit 7/Early 
Termination (Day 85). A score of 0 will be treated as missing data. 
7.1.3.2 
Clinical Global Impression - Change (CGI-C) 
The CGI-C is a 7-point scale that requires the clinician to rate the change of the patient's 
condition at the time of assessment, relative to the clinician's past experience with the 
patient's condition at admission. Ratings range from: 
0 =Not assessed 
1 =Very much improved 
2 =Much improved 
3 = Minimally improved 
4 =No Change 
5 =Minimally worse 
6 =Much worse 
7 =Very much worse. 
The CGI-C will be performed at Visit 4 (Day 43) to reflect changes from BaselineNisit 1 
(Day l); and Visit 7/Early Termination (Day 85) to reflect changes from both Visit 4 (Day 
43) and from BaselineNisit 1(Day1). A score of 0 will be treated as missing data. 
7.1.3.3 
Patient Global Impression - Change (PGIC) 
The PGIC is a 7-point patient-rated scale used to assess treatment response. Ratings range 
from: 
0 =Not assessed 
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1 =Very much improved 
2 =Much improved 
3 =Minimally improved 
4 =No Change 
5 =Minimally worse 
6 =Much worse 
7 =Very much worse. 
The PGIC will be performed at Visit 4 (Day 43) and Visit 7/Early Termination (Day 85), in 
both instances reflecting changes from BaselineNisit 1 (Day 1 ). A score of 0 will be treated 
as missing data. 
7.1.4 
Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS is a 9-item scale derived from the Hamilton Depression Scale (Ham-D), that is 
designed to assess depression specifically in patients with schizophrenia. Each item on the 
scale is scored as: 0 (absent); 1 (mild); 2 (moderate); 3 (severe). The CDSS score is 
obtained by adding each of the item scores; therefore ranges from 0 to 27. The CDSS will be 
performed at Screening, BaselineNisit 1 (Day 1), Visit 3 (Day 22), Visit 4 (Day 43), Visit 6 
(Day 64), and Visit 7/Early Termination (Day 85). The CDSS total score is a secondary 
efficacy endpoint. 
7.1.5 
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) 
The MCCB assesses cognitive change in trials of cognitive-enhancing agents in 
schizophrenia, and includes 10 tests that measure 7 cognitive domains: 
1. Speed of processing 
5. Visual learning 
2. Attention/vigilance 
6. Reasoning and problem solving 
3. Working memory 
7. Social cognition 
4. Verbal learning 
The MCCB evaluation will be performed at Screening, BaselineNisit 1 (Day 1 ), Visit 4 (Day 
43), and Visit 7/Early Termination (Day 85). Alternate versions of the battery will be used at 
different visits to decrease the learning confound. 
The composite score (T-score) is the secondary efficacy endpoint, with higher values 
indicating better cognitive performance. 
7.1.6 
Effort Expenditure for Reward Task (EEfRT) 
The EEfRT is a multi-trial computerized task in which participants are given an opportunity 
on each trial to choose between 2 tasks that differ in difficulty level and are associated with 
varying levels of monetary reward. This task examines willingness to expend physical effort 
(button pressing) in pursuit of varying amounts of monetary reward. 
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The ratio of hard task choices to the total number of trials, as well as the difference in 
proportion of hard-task choices for high effort vs. low effort trials will be the outcome 
measures for negative symptoms, and are secondary efficacy endpoints. The EEfRT 
evaluation will be performed at BaselineNisit 1 (Day 1), Visit 4 (Day 43), and Visit 7/Early 
Termination (Day 85). 
 
 
7.1.8 
Mini International Neuropsychiatric Interview (M.I.N.I.) Version 6.0.0 
The M.I.N.I. is an interview developed by psychiatrists and clinicians for psychiatric 
disorders and has an administration time of approximately 15 minutes. 
The interview is divided into 15 categories, which are listed below: 
• Major depressive episode 
• Substance dependence/abuse (non-
• Suicidality 
alcohol) 
• Manic and hypomanic episodes 
• Psychotic disorders and mood 
• Panic disorder 
disorder with psychotic features 
• Anorexia nervosa 
• Agoraphobia 
• Bulimia nervosa 
• Social phobia 
• Generalized anxiety disorder 
• Obsessive-compulsive disorder 
• Antisocial personality disorder 
• Posttraumatic stress disorder 
• Alcohol dependence/abuse 
Based on the answers, each category will be classified into a timeframe (e.g., current, past, 
etc.). Missing values will not be imputed. The M.I.N.I. is performed at Screening for the 
purpose of assessing whether the patient meets diagnostic criteria for schizophrenia residual 
type. Results will be presented in the data listings. 
7.1.9 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior and 
consists of a clinical interview, providing a summary of both suicidal ideation and behavior 
that will be used during treatment to monitor for clinical worsening. 
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Statistical Analysis Plan: 15-A VP-786-202 
The C-SSRS evaluation is a safety endpoint and will be performed at Screening, 
BaselineNisit 1 (Day 1), Visit 3 (Day 22), Visit 4 (Day 43), Visit 6 (Day 64), and Visit 
7 /Early Termination (Day 85). 
7.1.10 
Simpson Angus Scale for Extrapyramidal Symptoms (SAS) 
The SAS is a 10-item evaluation used to assess pseudoparkinsonism. Each item is graded on 
a 5-point severity scale; thus the total score ranges from 0 to 40, with higher scores indicating 
greater severity of extrapyramidal symptoms. 
The SAS evaluation is a safety endpoint and will be performed at BaselineNisit 1 (Day 1 ), 
Visit 4 (Day 43), and Visit 7/Early Termination (Day 85). 
7.1.11 
Barnes Akathisia Scale (BAS) 
The BAS is an assessment of the presence and frequency of akathisia (a movement disorder 
characterized by restlessness and a compulsion to move), as well as its global severity. The 
objective item of the scale measures the clinician's assessment of the patient's restlessness. 
The subjective portion of the scale measures both the patient's awareness ofrestlessness and 
the distress arising from such awareness. Each item is rated on a 4-point scale from 0 to 3, 
and the total score is the sum of the three item scores, thus yielding a total score ranging from 
0 to 9. The Global Clinical Assessment of Akathisia is rated on a 5-point scale from 0 to 4. 
Higher scores indicate greater severity of symptoms. 
The BAS evaluation is a safety endpoint and will be performed at BaselineNisit 1 (Day 1 ), 
Visit 4 (Day 43), and Visit 7/Early Termination (Day 85). 
7.1.12 
Abnormal Involuntary Movements Scale (AIMS) 
The AIMS is a 12-item scale to assess dyskinesia. Items related to the severity of orofacial, 
extremity, and trunk movements, global judgment about incapacitation, and patient 
awareness are rated using a 5-point scale (0 =None, 1 =Minimal, 2 =Mild, 3 =Moderate, 4 
= Severe). Two items related to dental status are scored using "yes/no" responses. 
The BAS evaluation will be performed at BaselineNisit 1 (Day 1), Visit 4 (Day 43), and 
Visit 7/Early Termination (Day 85). 
7.2 
Efficacy Endpoints 
The primary efficacy endpoint is the change from baseline (CFBL) in the NSA-16 total 
score. 
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Statistical Analysis Plan: 15-AVP-786-202 
Secondary endpoints are the CFBL (or actual scores for the CGI-C and PGIC) in the scores 
of the assessments listed below (and described above): 
• 
PANSS total score, PANSS subscales (positive, negative, general psychopathology, 
Marder negative factors, excitement component, and prosocial factors) 
• 
NSA-16 factor domains, global symptom/functioning score, individual items, and 
NSA-4 
• 
MCCB composite score 
• 
CGI-S, CGI-C, and PGIC scores 
• 
CDSS total score 
• 
EEfR T score 
In addition, the following secondary endpoint will be calculated: 
• 
Proportion of patients with a reduction of 20% or greater in the P ANSS total score 
7.3 
Safety Endpoints 
Safety and tolerability measurements will include: adverse events (AEs), vital signs, weight, 
urine pregnancy tests, clinical laboratory assessments, resting 12-lead ECGs, Columbia 
Suicide Severity Rating Scale (C-SSRS), Abnormal Involuntary Movements Scale (AIMS), 
Barnes Akathisia Scale (BAS), and Simpson Angus Scale for Extrapyramidal Symptoms 
(SAS). 
7.4 
Pharmacokinetic, 
 Parameters 
Plasma concentrations of d6-DM, its metabolites, Q, and anti psychotic medications will be 
assessed at BaselineNisit 1 (Day 1, post-dose), Visit 4 (Day 43), and Visit 7/Early 
Termination (Day 85). Corresponding Cmax and AUC values will be estimated. 
8 ANALYSIS POPULATIONS 
A summary table containing the number of patients in each of the populations described 
below will be provided. 
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Statistical Analysis Plan: 15-A VP-786-202 
8.1 
Modified Intent-to-Treat (mITT) Population 
The mITT Population will be used to analyze treatment efficacy according to the SPCD 
design. Due to the study design, the patients included in the population are determined 
separately for Stage 1 and Stage 2, although the Stage 2 group will be a subset of the Stage 1 
group. The population is defined below: 
• 
Stage 1: All patients randomized in Stage 1 who had at least one post-baseline NSA-
16 total score efficacy assessment in Stage 1. 
• 
Stage 2: All patients who were re-randomized into Stage 2 (regardless of Stage 1 
treatment group) and had at least one NSA-16 total score efficacy assessment in Stage 
2 (after Week 6Nisit 4) 
When implementing changes in Protocol Amendment 4, the IRT vendor who carried out the 
IVRS found that 14 Stage 1 Placebo patients were re-randomized for Stage 2 at Week 3 
instead of Week 6. These 14 patients with randomization error are excluded from the mITT 
analysis population. 
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8.3 
Safety Population 
The safety population will be used for all safety analyses. It includes all patients who 
received at least one dose of study medication. 
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9 OVERALL STATISTICAL CONSIDERATIONS 
9.1 
Definition of Baseline 
Baseline is generally defined as the last assessment prior to the first dose of study drug, but 
will vary depending on the analysis, population, treatment group, and parameter. See below 
for specific considerations: 
• 
For the primary efficacy analysis and secondary efficacy analyses on the mITT or PP 
populations, Stage 1 Baseline is the last assessment prior to first dose (or prior to 
randomization date, for patients who did not take study medication), which is 
typically Day 1. Stage 2 Baseline is the Visit 4 (Week 6) assessment 
(re-randomization visit). Note that Stage 2 Baseline only applies to patients who 
were randomized to placebo in Stage 1 and re-randomized in Stage 2. 
• 
Baseline for descriptive safety analyses are described below: 
o For patients receiving A VP-786 or placebo for the entire study duration, baseline 
is the last non-missing assessment prior to the first dose of study drug. 
o For patients randomized to placebo then re-randomized to A VP-786, Stage 1 
baseline is the last non-missing assessment to first dose of study drug and Stage 2 
baseline is the last non-missing assessment occurring after Day 1 and prior to 
re-randomization at Week 6. 
9.2 
Definition of End of Treatment 
End of treatment is defined as the last value for a given patient, whenever it occurred 
(including Stage 1 values). This terminology will not be used ifreferring to analysis that is 
done by study stage. 
9.3 
Change from Baseline 
Change from baseline (CFBL) will always be calculated as (post-baseline - baseline). It will 
be calculated for patients with both a baseline and post-baseline value as applicable. 
If a baseline value has not been recorded for a parameter, then CFBL will not be calculated 
for that parameter, and the patient will be excluded from CFBL analysis. 
Percent CFBL, when needed, is the CFBL divided by the baseline value multiplied by 100%. 
Patients with a value of 0 at baseline cannot have percent CFBL calculated. 
9.4 
Visit Windows 
Data at scheduled visits will be assigned to analysis visits as defined in the Visit Window 
tables below, to ensure that all visits have the potential to be included in the summaries. 
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Visit windows will be used to classify unscheduled and early termination visits. If 2 or more 
visits occur within the same analysis window, the value closest to the target day will be 
summarized. If the assessments are the same distance from the target day, the latest one will 
be used. 
Separate visit window tables are provided based on how frequently the assessments were 
done. Each table is also divided into patients who have advanced to Stage 2 and those that 
have not. 
Table 2. Visit Windows for Assessments Done at Baseline and Weeks 2, 3, 6, 8, 9, 12 
StageNisit 
Target 
Study Days (Patients 
Study Days (Patients Not 
Day 
Advancing to Stage 2) 
Advancing to Stage 2) 
Stage 1 
Lower Bound 
Upper Bound 
Lower Bound 
Upper Bound 
Week 2 (Visit 2) 
15 
2 
18 
2 
18 
Week 3 (Visit 3) 
22 
19 
ReR-2 
19 
32 
Week 6 (Visit 4) 
43 
ReR-1 
ReR 
33 
day of last visit 
Stage 2 
Stage 2 Baseline 
ReR-1 
ReR 
NIA 
NIA 
Week 8 (Visit 5) 
57 
ReR+ 1 
60 
NIA 
NIA 
Week 9 (Visit 6) 
64 
61 
74 
NIA 
NIA 
Week 12 (Visit 7) 
85 
75 
day of last visit 
NIA 
NIA 
NIA= Not applicable. ReR = re-randomization visit day. 
Table 3. Visit Windows for Assessments Done at Baseline and Weeks 3, 6, 9, and 12 
StageNisit 
Target 
Study Days (Patients 
Study Days (Patients Not 
Day 
Advancing to Stage 2) 
Advancing to Stage 2) 
Stage 1 
Lower Bound 
Upper Bound 
Lower Bound 
Upper Bound 
Week 3 (Visit 3) 
22 
2 
ReR-2 
2 
32 
Week 6 (Visit 4) 
43 
ReR-1 
ReR 
33 
day of last visit 
Stage 2 
Stage 2 Baseline 
ReR-1 
ReR 
NIA 
NIA 
Week 9 (Visit 6) 
64 
ReR+ l 
74 
NIA 
NIA 
Week 12 (Visit 7) 
85 
75 
day of last visit 
NIA 
NIA 
NIA= Not applicable. ReR =re-randomization visit day. 
Table 4. Visit Windows for Assessments Done at Baseline, Week 6, and Week 12 Only 
StageNisit 
Target 
Study Days (Patients 
Study Days (Patients Not 
Day 
Advancing to Stage 2) 
Advancing to Stage 2) 
Stage 1 
Lower Bound 
Upper Bound 
Lower Bound 
Upper Bound 
Week 6 (Visit 4) 
43 
2 
ReR 
2 
day of last visit 
Stage 2 
Stage 2 Baseline 
ReR-1 
ReR 
NIA 
NIA 
Week 12 (Visit 7) 
85 
ReR+ l 
day of last visit 
NIA 
NIA 
NIA= Not applicable. ReR =re-randomization visit day. 
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Statistical Analysis Plan: 15-A VP-786-202 
Table 2 applies to Vital Signs, Weight, C-SSRS; Table 3 applies to Pregnancy test, NSA-16, 
PANSS, CDSS; and Table 4 applies to ECG, Chemistry/Hematology/Urinalysis, SGA 
plasma concentrations, Study drug plasma concentrations, MCCB, CGI-S, CGI-C, PGIC, 
EEfRT, AIMS, BAS, SAS, 
. 
9.5 
Handling of Missing Data 
Missing data will be handled differently depending on the parameter and analysis. Note that 
analyses done on 'observed cases' will not follow any imputation rules below. See below for 
considerations: 
• 
Missing baseline values will not be imputed in any situation. 
• 
For SPCD 
 efficacy analyses (excluding observed cases 
analyses), missing data will be imputed by Last Observation Carried Forward (LOCF) 
within a study stage. For example, missing assessments from Week 12 (Visit 7) can 
be imputed with the value from Week 9 (Visit 6) but not from Week 3 (Visit 2). Note 
that if Week 3 or Week 6 data are missing for an mITT patient, then baseline will be 
carried forward. Likewise, Stage 2 baseline will be carried forward if Week 9 data 
are missing for patients with Stage 2 data. No imputation will be done for patients 
without data in Stage 2. 
• 
For any safety assessments of patients without a Week 12 safety endpoint assessment, 
the last non-missing post-baseline observation will be used as the end of treatment 
value. 
• 
Missing post-baseline values for by-visit safety data will be summarized using the 
Visit Windows from Section 9.4. If a value is not available within a given window, 
no imputation will be done. 
• 
Missing data for AE relationship will be imputed as "Related." 
• 
Rules for partial dates are described in Appendix 3. These will apply to concomitant 
medications when applicable. 
9.6 
Treatment Misallocations 
Efficacy data will be summarized "as randomized," meaning the patient will be summarized 
under the treatment they were randomized to, regardless of what treatment was actually 
received. 
Safety data will be summarized "as treated," meaning the patient will be summarized based 
on the treatment that was actually received. 
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9.7 
Summary Statistics 
Quantitative displays will be summarized using descriptive statistics. The mean, standard 
deviation, median, minimum, and maximum will be provided. Decimal precision will be 
based on the mean value. The median contains the same number of decimal places as the 
mean, the standard deviation contains one more decimal place, and the minimum and 
maximum contain one less decimal place. The mean will typically have one more decimal 
place than the raw values but if necessary, decimal precision for the mean will be provided in 
the table specifications. 
9.8 
Data Listings 
Unless otherwise specified, data listings will be provided on observed values and calculated 
PK parameters. Efficacy listings for the primary and secondary endpoints will include 
analysis flags and/or imputations to show which values were used in the summary tables. 
 
 
 Listings will be provided to serve as support for all summary tables 
or figures. 
9.9 
Graphical Displays 
Supporting figures may be used for some efficacy, PK or safety analyses in addition to the 
summary tables. Details regarding the content, layout, and structure of figures will be 
provided in the table specifications. 
9.10 
Hypothesis Testing 
All statistical testing will be 2-sided and performed at the 0.05 significance level. 
9.11 
Multiplicity of Secondary Endpoints 
No adjustments will be made for testing multiple secondary outcome measures. Since it is 
possible that some significant results could occur by chance alone, undue consideration will 
not be given to isolated significant differences; rather, interpretations will be made based on 
patterns of significant differences and their consistency with the primary endpoint analysis. 
10 EFFICACY STATISTICAL ANALYSIS METHODS 
The study schematic in Figure 1 can be referenced to identify treatment groups that are 
described in the subsequent efficacy sections. 
10.1 
Primary Efficacy: SPCD MMRM (Mixed-Model Repeated Measures) 
The primary efficacy endpoint (CFBL in NSA-16 total score), will be analyzed using a 
weighted test statistic with the treatment effects in each stage estimated by likelihood-based 
mixed-model repeated measures (MMRM) analysis on the observed data (Chen et al, 2011). 
This model will be run on the mITT population, which will include observed data from 
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Statistical Analysis Plan: 15-A VP-786-202 
Stage 1 mITT patients and from the Stage 1 Placebo Non-Responder Subset in Stage 2. Visit 
windows will be applied for unscheduled or early termination visits. The null hypothesis to 
be tested is that there will be no difference in the CFBL in NSA-16 total score between AVP-
786 and placebo in Stage 1 and Stage 2. 
Per the SPCD, separate MMRMs will be run using data from Stage 1 and Stage 2. Stage 1 
data (CFBL to Week 6) will contain data for all mITT Stage 1 patients and will compare 
study segments A and B from the study schematic. Stage 2 data (change from Week 6 to end 
of treatment) will be used for patients in the Stage 1 Placebo Non-responders of the Stage 2 
mITT population and will use study segments E and F. Stage 1 treatment effect will be 
estimated by Week 6 treatment difference and the Stage 2 treatment effect will be estimated 
by the Week 12 treatment difference. The model will include terms for treatment, visit, 
treatment-by-visit interaction, baseline NSA-16 value and baseline-by-visit interaction. An 
unstructured covariance matrix (UN) will be used. However, ifthere are convergence 
problems, analyses with a first-order autoregressive covariance structure (AR[l]) or the 
compound symmetry covariance structure (CS) will be used. The SAS model statement is 
provided below: 
The parameter estimates at Week 6 (Stage 1) and Week 12 (Stage 2) will be used in each 
stage to come up with a combined weighted test statistic, ZMMRM that is described in Chen, et 
al (2011 ). The formula for the test statistic is given below: 
W {j(l) + (1 - W) {j(Z) 
ZMMRM = ---;::=========== 
j w2 Var({JC1)) + (1 - w) 2 Vclr({JC2)) 
where a weight ofw = 
 is used for Stage 1, which means a weight of 1- w = 
 is used 
for Stage 2. The estimated treatment effects {}Cl), {}CZ) and squared standard errors 
Var({}Cl)), Var({}C2)) of each treatment stage are obtained directly from the model output. 
The test statistic will be used to come up with a 2-sided p-value for the hypothesis test, 
shown below: 
p_value=2*(1-probnorm(abs(ZMMRM))); 
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Statistical Analysis Plan: 15-A VP-786-202 
10.3 
Secondary Efficacy Analysis 
The following secondary endpoints will be analyzed in this study, using the methodologies 
described in the following subsections: 
• 
P ANSS total score 
• 
PANSS subscales (positive, negative, general psychopathology, Marder negative 
factors, excitement component, pro-social factors) 
• 
NSA-16 factor domains, global symptom/functioning score, individual items, global 
negative symptoms rating, and NSA-4 total score 
• 
Proportion of patients with a reduction of 20% or greater in the P ANSS total score 
• 
MCCB composite score 
• 
CGI-S, CGI-C, and PGIC scores 
• 
CDSS score 
• 
EEfRT score 
 
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Statistical Analysis Plan: 15-A VP-786-202 
10.3.1 
Secondary SPCD MMRM and SPCD OLS ANCOV A 
The CFBL for all quantitative secondary endpoints listed above (except the CGI-C and the 
PGIC) will be analyzed using the OLS ANCOV A method as described in Section 10.2. 1. 
The mITT population (Stage 1 plus the Stage 1 Placebo Non-Responders for Stage 2) will be 
used for these analyses. LOCF within a study stage will be used for missing values at Week 
6 or Week 12. In addition, the secondary endpoints listed above measured by NSA-16, 
PANSS and CDSS (which were assessed at Baseline, Week 3, 6, 9 and 12) will also be 
analyzed using the SPCD MMRM method as described in Section 10.1. 
For the CGI-C and the PGIC, an ANCOV A model with treatment as a factor and baseline 
NSA-16 total score as a covariate will be run. Note that baseline NSA-16 total score depends 
on the study stage and is defined in Section 9 .1 . All model considerations will be the same as 
the primary parameters as described in Section 10.1. 
10.3.2 
P ANSS Response Analysis 
The number and percent of patients who have favorable treatment responses according to the 
PANSS will be summarized at Week 6 and Week 12 using the mITT population (Stage 1 
plus the Stage 1 Placebo Non-responders in Stage 2). The following category will be used to 
classify patients: 
• 
Response: patients with at least a 20% reduction in the P ANSS total score. 
The number and percent of responders will be provided by stage and treatment group. LOCF 
will be used for patients missing data. Overall Stage 1 and 2 treatment differences will be 
tested via SPCD 1 degree of freedom (DOF) score test assuming Stage 2 and 1 treatment 
effect ratio p=l (A. Ivanova, et al, 2011). In addition, the treatment effect will also be tested 
at each visit by Chi-square test or Fisher's Exact (if the expected cell counts are< 5). 
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Statistical Analysis Plan: 15-A VP-786-202 
11 SAFETY STATISTICAL ANALYSIS METHODS 
Safety will be assessed through the analysis of AEs, physical and neurological examinations, 
vital signs, clinical laboratory assessments, ECGs, the C-SSRS, the SAS, the BAS, and the 
AIMS. All Safety analyses will be completed on the Safety Population. 
Unless otherwise specified, safety analyses that include summaries of number and percent 
(e.g., AEs) will be displayed using the following treatment groups: 
• 
Placebo/Placebo: patients receiving Placebo/Placebo during the study (study segment 
Al, C and E ). Note that patients randomized to Placebo/AVP-786 but dropped out in 
Stage 1 (part of A2) are not included in this population. Instead, these will be 
summarized under the 'All Placebo' treatment group. 
• 
A VP-786/ A VP-786: patients receiving A VP-786 for the entire duration of the study 
(Band G). 
• 
Placebo/ A VP-786: patients who switched from placebo to A VP-786. This group 
will be further divided into data that occurred while on placebo (A) and data that 
occurred while on AVP-786 (D and F). 
• 
All Placebo: This includes data from the stages when patients received placebo (A, 
C, and E). 
• 
All A VP-786: This includes data from the stages when patients received A VP-786 
(B, D, F, and G). 
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Statistical Analysis Plan: 15-A VP-786-202 
All Placebo and All A VP-786 treatment groups summarize the safety information for their 
corresponding treatment group under 6 week or 12 week treatment exposure in either Stage 
1, Stage 2, or both. 
For quantitative summaries (e.g., ECGs, labs), the All Placebo and All AVP-786 groups will 
not be included. As noted in Section 9 .1, baseline for safety assessments (excluding shift 
tables) is the last non-missing value prior to taking study drug at baseline. For those 
switching from placebo to A VP-786, baseline is the last non-missing value prior to taking 
AVP-786. 
11.1 
Adverse Events 
Adverse event tables (except the AE overview table) will only include summaries ofTEAEs. 
Treatment-emergent adverse events are defined as AEs which first occur, or worsen, after the 
first dose of study medication and within 3 0 days after the permanent discontinuation of the 
study medication (i.e., first dose date :SAE start date :S last dose date+ 30 days). 
An overview table containing the number and percent of the following will be included: 
• 
Number of total AEs, TEAEs, and deaths 
• 
Incidence of patients with at least one TEAE, drug-related TEAE, serious AE (SAE), 
drug-related SAE, non-serious TEAEs, and death 
• 
Incidence of patients who discontinued due to TEAE, drug-related TEAE, SAE, and 
drug-related Si'.ill 
• 
Incidence of deaths and deaths due to drug-related TEAE 
Treatment-emergent adverse events will be summarized by SOC and PT, descending 
frequency of PT, by maximum severity, by dose at onset, and by age group(< 45, 2: 45). 
Summaries of PTs will also be done for those occurring in at least 5% of patients in any 
treatment or study stage. In addition, summaries of patients taking beta blockers at baseline 
will be summarized as described in Section 10.4.6. 
Adverse events leading to discontinuation will be summarized by SOC and PT. Drug-related 
AEs will be summarized by SOC and PT and in descending frequency of PT. 
Time to onset for common TEAEs (as defined below) will be summarized descriptively for 
each of these events. In addition, summary stats for the duration and percentage of total 
study days will be provided for each AE. The number and percent of patients with 
recurrences will also be given. 
Serious adverse events will be summarized by SOC and PT and will include a summary of 
drug-related events. 
Below are the rules to follow for AE summaries: 
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Statistical Analysis Plan: 15-A VP-786-202 
• 
For patients who took A VP-786/ A VP-786 or Placebo/Placebo: If a patient has 
multiple AEs within the same SOC or PT, the patient will only be counted once 
within a level of Medical Dictionary for Regulatory Activities (MedDRA). 
• 
For patients who switched from placebo to AVP-786: If the same AE starts in both 
study stages, it should be counted under both placebo and A VP-786. 
• 
A drug-related AE is defined as an AE with an assigned relationship of "possibly 
related," "related," or missing. 
• 
When assessing severity, if a patient has 2 TEAEs within a study stage, the TEAE 
with the worst severity will be chosen. AEs with missing severity will be excluded 
from summaries of AE by severity. 
• 
For dose at onset summaries, patients are counted only once within a dose, but can be 
counted in multiple dose groups if the same AE occurred while on different doses. 
• 
A common TEAE is defined as a TEAE an incidence of2: 3% in the All AVP-786 
treatment group AND 2: 2 times the incidence of the All Placebo treatment group. 
• 
Time to onset will be calculated in days as (AE start date - first dose date). For 
patients who switched from placebo to A VP-786, the following rules will apply: 
o If an AE occurs when the patient is on A VP-786, time to onset is calculated as 
(AE start date - re-randomization date). This includes the time on A VP-786 only. 
o If the same AE occurs while the patient is on placebo and then again when the 
patient is on A VP-786, the AE will be counted in both groups, and first dose date 
will be defined as the first dose of placebo or first dose of A VP-786, depending 
on which treatment the patient was on when the AE occurred. 
• 
Duration of AE is generally defined as (AE end date-AE start date+ 1). Duration 
will be calculated for placebo and A VP-786 separately. Below are some additional 
considerations for AE duration: 
o If the patient has an AE on placebo that has not ended when the patient takes the 
last dose of placebo (either due to switching to A VP-786 or end of study), AE end 
date is defined as the last dose of placebo. 
o If the patient has an AE on A VP-786 that has not ended when the patient ends the 
study, AE end date is defined as the last dose of study drug. 
o If the same AE occurs more than once while the patient is on the same treatment, 
duration will be the sum of the individual AE durations. 
• 
For a given patient, percentage of total study days is defined as total duration (as 
defined above) divided by (last dose date - first dose date+ l) x 100%. 
• 
Recurrence is defined as a new report of the same TEAE with a new AE start date 
within a given treatment. An AE that occurs for a patient on placebo and then again 
on A VP-786 will not be considered a recurrent event. 
AEs will be coded using MedDRA version 18.1. 
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Statistical Analysis Plan: 15-A VP-786-202 
11.2 
Clinical Laboratory Assessments 
Clinical labs will be reported for hematology, chemistry and urinalysis. Labs are collected at 
Screening, Week 6 and Week 12, and will be summarized by visit, by stage and for the 
Placebo/Placebo and A VP-786/ A VP-786 groups as described below. 
The following parameters will be summarized descriptively through CFBL and percent 
CFBL for numeric values. If a parameter is categorical, it will be listed only. 
• 
Chemistry: calcium, magnesium, phosphorus, glucose, sodium, potassium, chloride, 
carbon dioxide, blood urea nitrogen (BUN), serum creatinine, uric acid, albumin, total 
bilirubin, alkaline phosphatase, lactate dehydrogenase (LDH), aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), alanine 
aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT), creatine kinase 
(CK), gamma-glutamyl transferase (GGT), triglycerides, total protein, total 
cholesterol, and glycosylated hemoglobin (HbAlc, at Screening and Visit 7). 
• 
Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell 
(WBC) count, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, 
platelet count, and morphology 
• 
Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, urobilinogen, 
nitrites, leucocytes, and blood 
Out-of-range values will be assessed through shift tables. Each lab value will be assessed as 
low, normal or high based on the normal ranges provided by the central lab. Frequencies of 
each combination of shifts will be provided by treatment group. 
Shift tables will be created by stage and for the Stage 1 Placebo, A VP-786, Stage 2 Placebo 
(Stage 1 Placebo re-randomized to Placebo) and Stage 2 A VP-786 (Stage 1 Placebo re-
randomized to A VP-786). In Stage 1, A VP-786 will be compared to placebo and in Stage 2, 
the placebo patients who were re-randomized to either A VP-786 or placebo will be 
compared. Baseline in all shift tables is the last assessment prior to first dose in each stage. 
Last post-baseline visit for Stage 1 is the last assessment prior to or on the Week 6 visit, 
while the last post-baseline visit in Stage 2 and the Placebo/Placebo, A VP-786/ A VP-786 
groups is the last assessment, whenever it occurred. 
 
 
Potentially clinically significant (PCS) tables will also be used to summarize out-of-range 
values. The PCS values are found in Table 5. The number and percent of patients meeting 
the criteria below will be summarized by treatment group. Summaries will be given for any 
time post-baseline. The denominator for the percentages will be the number of patients who 
had a post-baseline assessment for each parameter. 
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Statistical Analysis Plan: 15-A VP-786-202 
Table 5. Lab PCS Criteria 
Laboratory 
Low PCS 
High PCS 
Laboratory 
Low 
High PCS 
Unit 
Unit 
PCS 
Parameter 
Criteria 
Criteria 
Parameter 
Criteria 
Criteria 
Chemistry 
Albumin 
g/L 
:S26 
~ 60 
GGT 
U/L 
None 
~ 60 
Alkaline 
U/L 
None 
~3xULN 
Glucose 
mmol/L 
:S 2.775 
~ 11.1 
Phosphatase 
ALT (SGPT) 
U/L 
None 
~3xULN 
LDH 
U/L 
None 
~3xULN 
AST (SGOT) 
U/L 
None 
~3xULN 
Magnesium 
mmol/L 
< 0.37 
> 1.23 
Bilirubin 
µmol/L 
None 
~ I.5xULN 
Phosphate 
mmol/L 
:S 0.4522 
> 3.88 
BUN 
mmol/L 
None 
~ 10.71 
Potassium 
mmol/L 
:S3.0 
~ 5.5 
Calcium 
mmol/L 
:S 1.75 
~ 3.0 
Protein 
g/L 
:S 50 
~ 100 
Carbon 
mmol/L 
:S 9 
>40 
Sodium 
mmol/L 
:S 130 
~ 155 
Dioxide 
Chloride 
mmol/L 
:S 85 
~ 120 
Triglycerides 
mmol/L 
None 
> 3.39 
Cholesterol 
mmol/L 
None 
~ 7.77 
Uric acid 
µmol/L 
None 
~ 624.54 
(Male) 
Creatine 
U/L 
None 
~3xULN 
Uric acid 
µmol/L 
None 
~ 505.58 
Kinase 
(Female) 
Creatinine 
µmol/L 
None 
> 132.6 
HbAlc 
% 
None 
6.5% 
Hematology 
Hemoglobin 
g/L 
< 100 
> 180 
Monocytes 
xl09/L 
None 
> 1 
Hematocrit 
proportion 
< 0.3 
> 0.5 
Monocytes/ 
% 
None 
~ 15 
of 1.0 
Leukocytes 
Basophils 
xl09/L 
None 
> 0.3 
Neutrophils/ 
% 
:S 15 
None 
Leukocytes 
Eosinophils/ 
% 
None 
~ 10 
Leukocytes 
xl09/L 
:S 2.8 
~16 
Leukocytes 
Lymphocytes 
xl09/L 
:S 0.5 
>4 
Erythrocytes 
x 10 12/L 
:S2.5 
~ 7.0 
Lymphocytes/ 
% 
:S 10 
~ 60 
Platelet 
xl09/L 
:S 100 
~ 700 
Leukocytes 
Count 
Over the course of the study, there may be some lab tests performed that were not mentioned 
in the protocol. These tests will not be summarized but will be included in the listings and 
flagged as non-protocol tests. 
11.3 
ECGs 
Electrocardiograms will be assessed by a central reader and will be recorded at the following 
visits: 
• 
Screening (triplicate readings) 
• 
BaselineNisit I (Day 1) (pre-dose) 
• 
BaselineNisit I (Day I) (2-3 hours post-dose) 
• 
Visit 4/Week 6 (Day 43) (pre-dose) 
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Statistical Analysis Plan: 15-A VP-786-202 
• 
Visit 4/Week 6 (Day 43) (2-3 hours post-dose) 
• 
Visit 7/Early Termination (Day 85) (pre-dose) 
• 
Visit 7/Early Termination (Day 85) (2-3 hours post-dose) 
The following quantitative parameters will be reported by the central reader: heart rate, PR 
interval, QRS duration, QT interval (uncorrected), and QT interval with Fridericia's 
correction (QTcF). Change from baseline and percent change from baseline will be 
calculated for each parameter and summarized by the treatment groups mentioned in 
Section 11 . Note that for patients who switched from placebo to A VP-786, baseline is 
defined as described in Section 9 .1. 
In addition, since ECGs are recorded pre- and post-dose at Baseline, Week 6 and Week 12, 
change from pre- to post-dose will be summarized at these visits. 
PR interval and QTcF will be further investigated through PCS tables, for which the criteria 
are found in Table 6 below. The number and percent of patients meeting the criteria below 
will be summarized by treatment group. Summaries will be given for both overall (i.e., any 
time post-baseline) and by visit. For QTcF, males and females will be assessed separately. 
Patients will be included in all categories for which they qualify. For criteria on the "Actual" 
values, the denominator for the percentages is the number of patients who had a post-baseline 
assessment for each parameter. For criteria on the change, the denominator is the number of 
patients who had a baseline and post-baseline assessment. 
Table 6. ECG PCS Criteria 
ECG Parameter 
Sex 
Actual or Change 
PCS Criteria 
> 200 to :S 220, 
PR Interval (msec) 
Both 
Actual 
> 220 to :S 250, 
> 250 
> 450 to ::; 480, 
Males 
Actual 
> 480 to ::; 500, 
> 500 
QTcF (msec) 
> 460 to :S 485, 
Females 
Actual 
> 485 to :S 500, 
> 500 
Both 
Change from baseline (increase) 
:::: 30, :::: 60 
ECG overall interpretations will be summarized by the number and percent that were normal 
or abnormal. The interpretations by the cardiologist (i.e., central ECG, iCardiac) will be used 
for these summaries. For females, iCardiac uses QTcF > 460 msec to ::::; 485 msec for PCS 
criteria and this will be flagged in corresponding tables and listings. The listings will provide 
all interpretations and corresponding details. 
11.4 
Vital Signs 
Vital signs will be assessed at all visits. Orthostatic blood pressure is taken at Screening and 
supine/semi-recumbent blood pressure is taken at all subsequent visits. All 
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Statistical Analysis Plan: 15-A VP-786-202 
supine/semi-recumbent measurements are recorded twice, so the mean of the 2 measurements 
will be taken and used for all summaries mentioned below. The following parameters 
recorded in the supine/semi-recumbent positions will be summarized: systolic blood 
pressure (SBP), diastolic blood pressure (DBP), heart rate. Weight will also be summarized. 
These parameters will be summarized through CFBL and percent CFBL in similar fashion as 
the ECG parameters. For heart rate, SBP and DBP, box plots by visit will be presented for 
Stage 1 
 safety population. 
Vital signs will also be assessed through PCS criteria, which are given in Table 7. Patients 
will be counted if they meet the criteria below at any time post-baseline. The definition of 
baseline is consistent with those for ECG parameters. The denominators are the number of 
patients with both a baseline and post-baseline assessment. 
Table 7. Vital Sign PCS Criteria 
Vital Sign 
Parameter 
SBP (mmHg) 
DBP (mmHg) 
Pulse (bpm) 
SBP and pulse 
DBP and pulse 
High Values 
> 180 AND 2: 20 increase from baseline 
2: I 05 AND 2: 15 increase from baseline 
2: 120 AND 2: 15 increase from baseline 
SBP 2: I 0 increase from baseline AND pulse 2: 5 
increase from baseline 
DBP 2: 5 increase from baseline AND pulse 2: 5 
increase from baseline 
All vital sign parameters will be included in the listings. 
11.5 
Physical and Neurological Exams 
Low Values 
:S 90 AND 2: 20 decrease from baseline 
:S 50 AND 2: 15 decrease from baseline 
:S 50 AND 2: 15 decrease from baseline 
Not Applicable 
Not Applicable 
Physical and neurological exams are assessed at Screening and will be listed. 
11.6 
C-SSRS 
Scoring for the C-SSRS will be analyzed using the following indicators: 
• 
Ideation severity: each of the 5 questions regarding type of ideation (yes/no) 
• 
Intensity of most severe ideation: a sum of the 5 intensity items 
• 
Suicidal behavior types: each of the 4 suicidal behavior types (yes/no) 
• 
Suicidal behavior: suicidal behavior question 
• 
Actual lethality: actual lethality question (0-5 scale) on most lethal attempt 
• 
Potential lethality: potential lethality question (0-2 scale) on most lethal attempt 
The individual questions listed above that have yes/no responses will be summarized by 
treatment group and visit using number and percent. 
Intensity of most or severe ideation will be summarized descriptive by treatment group and 
visit. 
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Statistical Analysis Plan: 15-A VP-786-202 
Items that contain an ordinal response will be summarized both through descriptive statistics 
and number and percent. 
All C-SSRS data, including individual text descriptions (included as part of some questions), 
will be included in the listings. 
11.7 
Simpson Angus Scale for Extrapyramidal Symptoms (SAS) 
The individual items, as well as the total score, will be summarized. Descriptive statistics 
will be provided by treatment group and visit for males and females separately, as well as 
both sexes overall. For each item, a shift table of the number and percent of patients in each 
score (0 to 4) from Baseline to Week 6 and Baseline to Week 12 will be summarized overall 
and for males and females separately. 
11.8 
Barnes Akathisia Scale (BAS) 
The objective assessment, subjective awareness, subjective distress, and global clinical 
assessment, as well as the total score, will be summarized. Descriptive statistics will be 
provided by treatment group and visit for males and females separately, as well as both sexes 
overall. Shift tables of the number and percent of patients of the total score and the global 
clinical assessment will be presented for Baseline to Week 6 and Baseline to Week 12, for 
males and females separately as well as both sexes overall. 
11.9 
Abnormal Involuntary Movement Scale (AIMS) 
The following table represents the scores to be calculated and summarized: 
Subscale/Score 
Item Numbers 
Score Range 
Orofacial Movements 
1, 2, 3, 4 
0-16 
Extremity Movements 
5, 6 
0-8 
Trunk Movements 
7 
0-4 
Global Judgment 
8, 9, 10 
0-12 
Dental Status 
11, 12 
Yes/No 
Observed Movements 
1-7 
0-28 
Overall Severity 
8 
0-4 
Descriptive statistics will be provided by treatment group and visit for males and females 
separately, as well as both sexes overall. Shift tables of the number and percent of patients 
will be presented for Baseline to Week 6 and Baseline to Week 12 for the overall severity, 
for males and females separately as well as both sexes overall. 
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Statistical Analysis Plan: 15-A VP-786-202 
12 ADDITIONAL STATISTICAL ANALYSIS METHODS 
12.1 
Patient Disposition 
Counts of patient enrollment will provide the number of patients screened along with the 
reason for screen failures. A summary of randomized treatment group by responder status 
will be provided. Patient status will be summarized by the following: 
• 
Randomized in Stage 1 
• 
Took study medication 
• 
Discontinued during each stage 
• 
Re-randomized to Stage 2 
• 
Completed study 
Counts will be provided by Stage 1 randomized treatment group based on the study stage. 
Primary reasons for discontinuation will be provided based on the number of patients in the 
treatment group and stage. 
An overall number of patients by stage in the mITT, 
 and 
Safety populations will be provided. 
12.2 
Demographics and Baseline Characteristics 
Demographics will be summarized by randomized treatment group and overall for the mITT, 
and Safety populations. The following characteristics will be summarized. 
• 
Sex (Male, Female) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Age 
• 
Age group(< 55, 2 55) 
• 
Height 
• 
Weight 
• 
Body mass index 
A summary of baseline characteristics will include baseline values of all primary and 
secondary endpoints, in addition to height, weight, and body mass index. These will be 
summarized by randomized treatment group. Additional tables of primary and secondary 
endpoints for placebo non-responders and placebo responders will be created. Stage 2 
baseline will be used for these patients. 
For categorical parameters, the denominators for the percentages are the number of patients 
who had the parameter assessed. 
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Statistical Analysis Plan: 15-A VP-786-202 
12.3 
Medical History and Disease Characteristics 
Medical history will be summarized by SOC and PT based on Stage 1 randomization and 
will be presented in the listings. Summary tables will be provided for the frequency and 
percentage of patients by the following subgroups: 
• 
MCCB score< 30 versus 2: 30 
• 
Baseline concomitant benzodiazepine, SSRI, and SSNI medication use (Yes/No) 
Additionally, descriptive statistics for the number of years since the onset of schizophrenia, 
and the number of years since the onset of residual schizophrenia, will be presented. In both 
cases, the number of years will be counted relative to the patient's randomization date in 
Stage 1. 
12.4 
Exposure and Treatment Compliance 
Duration of exposure will be summarized quantitatively using the number of days on study 
medication for each patient, displayed by treatment group. Summaries will be done for 
Placebo/Placebo, A VP-786/ A VP-786, and each arm of the Placebo/ A VP-786 group. 
Duration for the Placebo/Placebo and A VP-786/ A VP-786 groups will be calculated as (last 
dose date - first dose date+ 1 ). For Stage 1 Placebo/ A VP-786 (placebo portion), duration 
will be calculated from first dose until the day prior to re-randomization, i.e., (re-
randomization date - first dose date). For Stage 2 (A VP-786 portion), duration will be 
calculated from re-randomization to last dose date, i.e., (last dose date - re-randomization 
date+ 1). 
An additional summary of exposure will be provided by dose taken for patients who took 
A VP-786 at any time during the study. The number of days at the specified dose level will 
be summarized. Treatment groups will be A VP-786/ A VP-786 and Placebo/ A VP-786. Since 
the dosing regimen increases after one week on treatment but a visit does not occur for 2 
weeks after starting treatment, it is assumed that each dose level is taken for 7 days, as 
specified in the protocol. Doses summarized will be 
 mg QD, 
 mg BID and 34 mg BID. 
The dosing regimen can be found in Figure 1. 
Overall treatment compliance will be calculated as a percentage using the total number of 
capsules that were dispensed and returned. Patients will be grouped into categories of 
< 80%, 80% to 120%, > 120%. Counts will be summed over the visits for each patient to 
calculate an overall compliance value. 
Compliance will be summarized as described above and through descriptive statistics for 
Placebo/Placebo, A VP-786/ A VP-786, and each arm of the Placebo/ A VP-786 group. The 
number of doses taken and number of doses should have taken are necessary to calculate 
compliance. The calculation for number of doses should have taken will be slightly different 
for patients who were randomized vs. those who were not re-randomized, as well as between 
Stage 1 and Stage 2. These differences are provided in the table below. The 3 steps for 
calculating compliance are shown here: 
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Statistical Analysis Plan: 15-A VP-786-202 
I. Doses taken: dispensed amount - returned amount 
2. Doses should have taken: 
Stage 
Stage I 
Stage 2 
Overall 
Patients Re-randomized 
2 x (re-randomization day - first dose day) 
2 x (last dose day - re-randomization day) +I 
2 x (last dose day - first dose day) + I 
Patients Not Re-randomized 
2 x (last dose day - first dose day) + I 
NIA 
2 x (last dose day - first dose day) + I 
3. Compliance = (doses taken I doses should have taken) x I 00% 
For the calculations in table above, the formulas are based on the assumption that patients 
take 2 capsules per day except for the last day, in which they only take I. One exception is 
for the Stage I calculation of patients who were re-randomized. For these patients, I is not 
subtracted because they will take 2 capsules on the last day of Stage I. 
The number of capsules taken for kits that were not returned will be imputed to be the 
number of capsules that were dispensed. 
12.5 
Prior and Concomitant Medications 
The number and percent of prior and concomitant medications will be provided by the 
treatment groups used for the safety analyses. Prior medication is defined as medication with 
a stop date prior to first dose date. Concomitant medication is defined as a medication with a 
start date on or before the last dose date AND a stop date on or after first dose date. 
Medication that is ongoing at the time of first dose is also considered concomitant. Partial 
dates will be imputed using rules in Appendix 3. 
Prior and concomitant medications will be coded using WHO Drug Dictionary (version 
September 20I5). Summaries will be provided by anatomical therapeutic chemical 
classification (ATC) and preferred term. 
12.6 
Analysis of Pharmacokinetics and Pharmacodynamics 
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Statistical Analysis Plan: 15-AVP-786-202 
13 ADDITIONAL STATISTICAL CONSIDERATIONS 
13.1 
Data Safety Monitoring Board (DSMB) 
There is no DSMB for this study. 
13.2 
Changes from Protocol 
When implementing changes in protocol amendment 4, the IRT vendor who carried out the 
IVRS found that 14 Stage 1 Placebo patients were re-randomized for Stage 2 at Week 3 
instead of Week 6. These 14 patients with randomization error are excluded from the mITT 
and ITT analysis population although they satisfied protocol mITT and ITT population 
criteria. Their safety data are summarized under safety population and their efficacy data are 
included in the corresponding data listings. 
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Statistical Analysis Plan: 15-A VP-786-202 
14 REFERENCES 
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Statistical Analysis Plan: 15-A VP-786-202 
15 APPENDICES 
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Statistical Analysis Plan: 15-A VP-786-202 
Appendix 1 Schedule of Assessments and Procedures 
Stage 1 
I 
Stage 2 
Visit 
Screening 
Baseline Phone' Visit22 Visit3 1 Visit 42 Phone' Visit52 Visit6 1 
Visit 
Post Exit 
Visit 1 
7/ET2•4 
Phone' 
PROCEDURE 
Study Day 
Day-28 to -7 
Day 1 
Day8 
Day 15 
Day22 Day43 Day SO 
Day57 Day64 
Day85 
Day 86-90 
Study Week Week-4 to -1 
Week 1 Week2 Week3 Week6 Week? Week8 Week9 Week 12 
Informed Consent 
x 
 
x 
x 
Medical History 
x 
M.I.N.I. Exam 
x 
Inclusion and Exclusion 
x 
x 
Randomization I (re-
x 
x 
randomization) 
Physical Examination 
x 
Resting 12-lead ECG 
x6 
x6 
x6 
x6 
Chemistry, Hematology, and 
x 
x 
x 
Urinalysis3 
Pregnancy Test 3 
x 
x 
x 
x 
x 
x 
 
xs 
Plasma Antipsychotic Levels 
x 
x 
x 
PK and 
 
xs 
xs 
xs 
 
Review of Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record Vital Signs/Weight9 
x 
x 
x 
x 
x 
x 
x 
x 
NSA-16 
x 
x 
x 
x 
x 
x 
PANSS 
x 
x 
x 
x 
x 
x 
MCCB 10 
x 
x 
x 
x 
CGI-S 
x 
x 
x 
COSS 
x 
x 
x 
x 
x 
x 
CGI-C 
x 
x 
PGIC 
x 
x 
RDoC Task (EEfRT) 
x 
x 
x 
Side Effects Scales 
x 
x 
x 
(AIMS, BAS, SAS) 
C-SSRS 
x 
x 
x 
x 
x 
x 
x 
x 
Dispense Study Medication 
x 
x 
x 
x 
Dose in Clinic 
x 
x 
x 
x 
x 
x 
x 
Review and/or Return Unused 
xs 
x 
x 
x 
xs 
x 
x 
x 
Study Medication 
.. 
I. V1s1ts 3 and 6 have a +3 day window. 
2. Visits 2, 4, 5, and 7 have a ±3 day window. 
3. Urinary (beta-hCG) test will be performed for all females regardless of childbearing potential (serum beta-hCG at Screening only). Fasting 
glucose and lipids will be measured at Screening, Visit 4, and Visit 7/ET. 
4. 
Final visit or Early Termination Visit for patients who withdraw prior to study completion. 
5. 
PK blood draws will be taken 2-3 hours post-dose for Baseline, Visit 4, and Visit 7/ET. 
 
 
 
6. Electrocardiogram will be performed prior to dosing and 2-3 hours post-dosing for Visits 1 and 4. Post-dose only for Visit 7. Triplicate 
ECGs at Screening only. 
7. 
Telephone call will have a +3 day window. Post study exit calls will be daily for S days to assess any changes in health (AEs)/concomitant 
medications. 
8. Patient will be asked if they have taken their medications as directed during telephone calls on Days 8 and SO. 
9. Height will be measured at Screening only. 
10. The MCCB should be conducted at approximately the same time of day(+/- 2 hours) and preferably in the AM. After the Screening Visit, 
patients who use sedatives/hypnotics or benzodiazepine medications on a pm basis should not take any of these medications the day of, or 
the day before, the assessment of cognitive function by MCCB. Patients who are on stable dose regimens of sedatives/hypnotics or 
benzodiazepine medications should take their medication as prescribed. 
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Statistical Analysis Plan: I 5-A VP-786-202 
 
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Statistical Analysis Plan: 15-A VP-786-202 
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Statistical Analysis Plan: 15-A VP-786-20 
Appendix 3 Prior and Concomitant Medication Start Date Imputation 
Imputation Rules for Partial Dates (D =day, M =month, Y =year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
Donly 
M and Y same as M and Y of first 
Date of first dose of study drug 
con meds 
dose of study drug 
Mand/or Y not same as date of first 
First day of month 
dose of study drug 
MandD 
Y same as Y of first dose of study drug 
Date of first dose of study drug 
Y not same as Y of first dose of study 
Use Jan 01 ofY 
drug 
M, D, and Y 
None - date completely missing 
Day prior to date of first dose 
of study drug 
Stop date for 
D only 
M and Y same as M and Y of last dose 
Date of last dose of study drug 
con meds 
of study drug 
M and/or Y not same as date of last 
Last day of month 
dose of study drug 
MandD 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study 
Use Dec 31 ofY 
drug 
M, D, and Y 
None - date completely missing and 
Date of last dose of study drug 
NOT ongoing 
Note: In all cases, ifan estimated start date is after a complete stop date, use the first day of the stop date 
month. 
Similarly, ifthe estimated stop date is before a complete or imputed start date, use the last day of the start 
day month. 
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Statistical Analysis Plan: 15-A VP-786-202 
 
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Statistical Analysis Plan: 15-A VP-786-202 
Appendix 5 List of Selective Serotonin-norepinepherine Reuptake Inhibitors (SNRis) 
Preferred Term 
Trade Names 
V enlafaxine 
Efexor, Effexor 
Sibutramine 
Meridia, Reductil 
Duloxetine 
Cymbalta, Ariclaim, Xeristar, Y entreve 
Atomoxetine 
Strattera 
Desvenlafaxine 
Pristiq 
Milnacipran 
Savella, Ixel, Dalcipran, Toledomin 
Levomilnaci pran 
Fetzima 
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