A Phase 3, Multicenter, Long Term, Extension Study of the Safety and Efficacy of AVP-786 (Deuterated [d6] Dextromethorphan Hydrobromide [d6-DM]/Quinidine Sulfate [Q]) for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type
Phase: PHASE3
Conditions: Agitation in Patients With Dementia of the Alzheimer's Type
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.



CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 2
TABLE OF CONTENTS 
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................5
LIST OF FIGURES .........................................................................................................................5
LIST OF ABBREVIATIONS..........................................................................................................6
PROTOCOL AGREEMENT...........................................................................................................9
STUDY SYNOPSIS ......................................................................................................................10
1.
BACKGROUND AND CLINICAL RATIONALE...................................................21
2.
STUDY OBJECTIVES ..............................................................................................23
3.
STUDY DESIGN .......................................................................................................24
4.
STUDY POPULATION.............................................................................................25
4.1.
Inclusion Criteria ........................................................................................................25
4.2.
Exclusion Criteria.......................................................................................................27
4.3.
Patient Withdrawal From the Study ...........................................................................28
5.
STUDY TREATMENTS............................................................................................30
5.1.
Treatments Administered............................................................................................30
5.1.1.
Description of Study Medications ..............................................................................30
5.1.2.
Composition of AVP-786...........................................................................................30
5.1.3.
Packaging....................................................................................................................30
5.1.4.
Labeling......................................................................................................................31
5.1.5.
Storage of Clinical Supplies .......................................................................................31
5.1.6.
Study Medication Administration...............................................................................31
5.2.
Accountability of Study Supplies...............................................................................32
5.2.1.
Receipt of Supplies.....................................................................................................32
5.2.2.
Record of Dispensing .................................................................................................32
5.2.3.
Unused Supplies .........................................................................................................32
5.3.
Methods of Assigning Patients to Treatment Groups.................................................32
5.3.1.
Treatment Assignment................................................................................................32
5.3.2.
Blinding/Masking .......................................................................................................33
5.3.3.
Treatment Dose Adjustment.......................................................................................33
5.4.
Patient Compliance.....................................................................................................33
5.5.
Concomitant Medications and Nondrug Therapies....................................................33
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 3
5.5.1.
Allowed Concomitant Medications for the Treatment of AD, Agitation, 
Depression, Insomnia, and Behavioral Disturbances .................................................34
5.5.2.
Rescue Medication for the Symptoms of Agitation ...................................................35
5.5.3.
Prohibited Concomitant Medications .........................................................................35
5.5.4.
Nondrug Therapies .....................................................................................................35
5.5.5.
Nonpharmacological Interventions for the Treatment of Agitation ...........................35
6.
STUDY ASSESSMENTS AND PROCEDURES......................................................36
6.1.
Screening/Baseline Only Procedures..........................................................................36
6.1.1.
Timed Up and Go (TUG) Test....................................................................................36
6.1.2.
Cornell Scale for Depression in Dementia (CSDD)...................................................36
6.2.
Safety..........................................................................................................................37
6.2.1.
Adverse Events...........................................................................................................37
6.2.2.
Physical and Neurological Examinations...................................................................39
6.2.3.
Vital Signs ..................................................................................................................40
6.2.4.
Clinical Laboratory Tests ...........................................................................................40
6.2.5.
Pregnancy Tests..........................................................................................................41
6.2.6.
Electrocardiograms.....................................................................................................41
6.2.7.
Sheehan Suicidality Tracking Scale (S-STS) .............................................................42
6.2.8.
Mini-Mental State Examination (MMSE)..................................................................42
6.2.9.
Epworth Sleepiness Scale (ESS) ................................................................................42
6.3.
Efficacy.......................................................................................................................43
6.3.1.
Cohen-Mansfield Agitation Inventory (CMAI)..........................................................43
6.3.2.
Neuropsychiatric Inventory (NPI) Agitation/Aggression, Irritability/Lability, 
and Aberrant Motor Behavior Domains .....................................................................43
6.3.3.
Clinical Global Impression of Severity of Illness (CGIS-Agitation) .........................44
6.3.4.
Modified Alzheimer’s Disease Cooperative Study - Clinical Global 
Impression of Change Rating (mADCS-CGIC-Agitation).........................................44
6.3.5.
Patient Global Impression of Change (PGIC) ............................................................45
6.3.6.
Dementia Quality of Life (DEMQOL).......................................................................45
6.3.7.
Resource Utilization in Dementia (RUD)...................................................................45
6.3.8.
EuroQol 5-Dimension 5-Level (EQ-5D-5L) ..............................................................46
6.4.
Schedule of Evaluations and Procedures....................................................................46
6.4.1.
Description of Study Procedures ................................................................................47
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
3

C O N FI D E N TI A L A N D P R O P RI E T A R Y
Pr ot oc ol 1 5- A V P- 7 8 6- 3 0 3
A me n d me nt 7, Versi o n 8. 0
O P D C
A V P- 7 8 6
Pa ge 4
6. 4. 2. 
E n d of Trial................................................................................................................. 5 9
7.  
D A T A M A N A G E M E N T ........................................................................................... 6 0
7. 1.  
Data C ollecti o n........................................................................................................... 6 0
8. 
S T A TI S TI C A L M E T H O D S....................................................................................... 6 1
8. 1.  
A nal ysis P o p ulati o n.................................................................................................... 6 1
8. 2.  
De m o gra p hic a n d Baseli ne C haracteristics................................................................ 6 1
8. 3. 
Safet y A nal ysis........................................................................................................... 6 1
8. 4. 
Efficac y A nal ysis........................................................................................................ 6 1
8. 5. 
I nteri m A nal ysis.......................................................................................................... 6 1
8. 6. 
Sa m ple Size Calc ulati o ns ........................................................................................... 6 2
9.  
A D MI NI S T R A TI V E P R O C E D U R E S....................................................................... 6 3
9. 1. 
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee A p pr o val........................................... 6 3
9. 2. 
I nf or me d C o nse nt F or m.............................................................................................. 6 3
9. 3. 
Patie nt’s Diar y Car d ................................................................................................... 6 3
9. 4. 
Electr o nic Case Re p ort F or ms.................................................................................... 6 3
9. 5.  
Q ualit y Ass ura nce....................................................................................................... 6 4
9. 5. 1.  
D oc u me ntati o n............................................................................................................ 6 4
9. 5. 2.  
M o nit ori n g.................................................................................................................. 6 4
9. 6. 
Rec or d Rete nti o n........................................................................................................ 6 5
9. 7. 
S o urce Data................................................................................................................. 6 5
9. 8.  
Data Ha n dli n g............................................................................................................. 6 5
9. 9. 
La b orat or y Pr oce d ures................................................................................................ 6 5
9. 1 0.  
G ui deli nes f or G o o d Cli nical Practice........................................................................ 6 5
9. 1 1. 
C o n diti o ns f or A me n di n g t he Pr ot oc ol....................................................................... 6 5
9. 1 2. 
C o n diti o ns f or Ter mi nati n g t he St u d y........................................................................ 6 6
9. 1 3. 
C o nfi de ntialit y of St u d y D oc u me nts a n d Patie nt Rec or ds......................................... 6 6
9. 1 4. 
Re p orts........................................................................................................................ 6 6
9. 1 5. 
P u blicati o ns................................................................................................................. 6 6
9. 1 6.  
A u dits/I ns pecti o ns ...................................................................................................... 6 6
1 0. 
R E F E R E N C E S........................................................................................................... 6 8
1 1. 1. 
Pr ot oc ol A me n d me nt 7 ( Versi o n 8. 0) – 2 6 Ja n 2 0 2 2 ................................................. 7 2
A b bre vi ate d Cli nic al St u d y Re p ort 1 5- A V P- 7 8 6- 3 0 3
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
4
C C
I

CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 5
11.2.
Protocol Amendment 6 (Version 7.0) – 01 FEB 2021 ...............................................73
11.3.
Protocol Amendment 5 (Version 6.0) - 23 OCT 2017 ...............................................81
11.4.
Protocol Amendment 4 (Version 5.0) - 28 FEB 2017................................................87
11.5.
Protocol Amendment 3 (Version 4.0) - 16 MAY 2016..............................................89
11.6.
Protocol Amendment 2 (Version 3.0) - 01 OCT 2015 ...............................................92
11.7.
Protocol Amendment 1 (Version 2.0) - 01 JUL 2015 ................................................96
12.
APPENDICES............................................................................................................98
APPENDIX 1.
PROHIBITED CONCOMITANT MEDICATIONS .........................................99
LIST OF TABLES
Table 1
Schedule of Evaluations and Visits for Patients Enrolling Directly from 
Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305.........................13
Table 2
Schedule of Evaluations and Visits for Patients Who Delay Enrollment...................17
Table 3
Composition of Investigational Product.....................................................................30
LIST OF FIGURES
Figure 1
Sample Configuration of Investigational Product Blister Card..................................31
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 6
LIST OF ABBREVIATIONS
Abbreviation
Definition
AA
Alzheimer’s Association
AE
Adverse event
AD
Alzheimer’s Disease
ADCS
Alzheimer’s Disease Cooperative Study
ADWG
Agitation Definition Work Group
ALT/SGPT
Alanine aminotransferase/serum glutamic-pyruvic transaminase
AST/SGOT
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase
BID
Twice daily
BP
Blood pressure
BUN
Blood urea nitrogen
CD-ROM
Compact disc read-only-memory
CFR
Code of Federal Regulations
CitAD
Citalopram study for Agitation in Alzheimer’s disease
CGIC
Clinical Global Impression of Change
CGIS-Agitation
Clinical Global Impression of Severity of Illness scale for Agitation
CK
Creatine kinase
CMAI
Cohen-Mansfield Agitation Inventory
COVID-19
Coronavirus Disease 2019
CNS
Central nervous system
CRO
Contract research organization
CSDD
Cornell Scale for Depression in Dementia 
CYP
Cytochrome P450
d6-DM
Deuterated (d6)-dextromethorphan hydrobromide (or free base form)
DEMQOL
Dementia Quality of Life 
DM
Dextromethorphan hydrobromide
DMP
Data management plan
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text 
Revision
EC
Ethics Committee
ECDEU
Early Clinical Drug Evaluation Unit
ECG
Electrocardiogram
eCRF
Electronic case report form
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 7
Abbreviation
Definition
EDC
Electronic data capture
EP
European Pharmacopeia
EQ-5D-5L
EuroQol 5-Dimension 5-Level
ESS
EtM
Epworth Sleepiness Scale
Events to Monitor
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
HbA1c
Glycosylated hemoglobin 
HR
Heart rate
ICF
Informed consent form
ICH
International Council for Harmonisation
IP
Investigational product
IPA
International Psychogeriatric Association
IRB
Institutional Review Board
IWRS
Interactive Web Response System
LDH
Lactate dehydrogenase
mADCS-CGIC-
Agitation
Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of 
Change for Agitation
MAOI
Monoamine oxidase inhibitor
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini-Mental State Examination
NF
National Formulary
NIA
National Institute on Aging
NINCDS-ADRDA
National Institute of Neurological and Communicative Disorders and Stroke and 
Alzheimer’s Disease and Related Disorders Association
NPI
Neuropsychiatric Inventory
NPI-NH
Neuropsychiatric Inventory - Nursing Home version
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
OTC
Over–the-counter
PGIC
Patient Global Impression of Change
pH
Potential hydrogen
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 8
Abbreviation
Definition
PK
Pharmacokinetics
PR
The P-R interval from an ECG tracing
Q
Quinidine sulfate (or free base form)
QRS
The Q-R-S complex 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
RUD
Resource Utilization in Dementia
SAE
Serious adverse event
SAER
Serious Adverse Event Reporting
SDV
Source data verification
SNRI
Serotonin-norepinephrine reuptake inhibitor
SOC
System organ class
SPCD
Sequential Parallel Comparison Design
SSRI
Selective serotonin reuptake inhibitor
S-STS
Sheehan Suicidality Tracking Scale
T3
Triiodothyronine
T4
Thyroxine
TCA
Tricyclic antidepressant
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
TUG
Timed Up and Go
USP
United States Pharmacopoeia
WBC
White blood cell
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
8

C O N FI D E N TI A L A N D P R O P RI E T A R Y
Pr ot oc ol 1 5- A V P- 7 8 6- 3 0 3
A me n d me nt 7, Versi o n 8. 0
O P D C
A V P- 7 8 6
Pa ge 9
P R O T O C O L A G R E E M E N T
Pr ot oc ol Title:
A P hase 3, M ultice nter, L o n g-ter m, E xte nsi o n St u d y of t he Safet y a n d Efficac y of A V P- 7 8 6 
( de uterate d [ d 6] de xtr o met h or p ha n h y dr o br o mi de [ d 6- D M]/ q ui ni di ne s ulfate [ Q]) f or t he 
Treat me nt of A gitati o n i n Patie nts wit h De me ntia of t he Alz hei mer’s T y pe
Pr ot oc ol N u m ber: 1 5- A V P- 7 8 6- 3 0 3 ( A me n d me nt 7, 2 6 J a n 2 0 2 2)
T his d oc u me nt is a c o nfi de ntial c o m m u nicati o n of Ots u ka P har mace utical De vel o p me nt & 
C o m mercializati o n, I nc ( O P D C). T he reci pie nt a grees t hat n o u n p u blis he d i nf or mati o n c o ntai ne d 
wit hi n t his d oc u me nt or pr ot oc ol will be discl ose d or p u blis he d wit h o ut pri or c o nse nt a n d writte n 
a p pr o val fr o m O P D C. A n e xce pti o n t o t his a gree me nt ma y be ma de f or t he p ur p oses of et hical or 
re g ulat or y re vie w, i n w hic h case t his d oc u me nt ma y be discl ose d t o a n Et hics Re vie w B oar d or 
a n y a ut h orize d re prese ntati ve of a nati o nal a ut h orit y as re q uire d b y re g ulati o n.
T he si g nat ures of t he pri nci pal i n vesti gat or a n d re prese ntati ve of t he s p o ns or bel o w c o nstit ute 
t heir a p pr o val of t his pr ot oc ol a n d f urt her pr o vi de t he necessar y ass ura nces t hat:
1.
T his st u d y will be c o n d ucte d acc or di n g t o G o o d Cli nical Practice ( G C P) a n d t o all 
sti p ulati o ns, as s pecifie d i n b ot h cli nical a n d a d mi nistrati ve secti o ns of t he pr ot oc ol 
i ncl u di n g t he Declarati o n of Helsi n ki.
2.
T he c o n d uct a n d res ults of t his st u d y will be ke pt c o nfi de ntial, a n d t he electr o nic case 
re p ort f or ms (e C R Fs) a n d ot her perti ne nt data will bec o me t he pr o pert y of O P D C.
3.
T he pr ot oc ol c o ntai ns all necessar y i nf or mati o n re q uire d t o c o n d uct t he st u d y, as o utli ne d 
i n t he pr ot oc ol, a n d t hat t he st u d y will n ot be i nitiate d wit h o ut t he a p pr o val of a n 
a p pr o priate I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee (I R B/ E C).
4.
All partici pa nts i n t his st u d y will pr o vi de writte n i nf or me d c o nse nt i n acc or da nce wit h 
t he re q uire me nts s pecifie d i n t he C o de of Fe deral Re g ulati o ns ( 2 1 C F R Parts 5 0, 5 6, 3 1 2) 
a n d/ or t he Declarati o n of Helsi n ki. All partici pa nts will als o be i nf or me d t hat t heir 
me dical rec or ds will be ke pt c o nfi de ntial e xce pt f or re vie w b y O P D C or its 
re prese ntati ves, t he U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A), a n d ot her re g ulat or y 
a ge ncies as a p plica ble.
Pri nci pal I n vesti gat or Si g nat ure
Date
Pri nci pal I n vesti gat or Na me: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
O P D C Re prese ntati ve Si g nat ure
Date
O P D C Re prese ntati ve Na me:  
, M D
A b bre vi ate d Cli nic al St u d y Re p ort 1 5- A V P- 7 8 6- 3 0 3
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
9
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CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 10
STUDY SYNOPSIS
Title: A Phase 3, Multicenter, Long-term, Extension Study of the Safety and Efficacy of 
AVP-786 (deuterated [d6] dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for 
the Treatment of Agitation in Patients with Dementia of the Alzheimer’s Type.
Study Objectives
The objectives of the study are to evaluate the long-term safety and maintenance of efficacy of 
AVP-786 for the treatment of agitation in patients with dementia of the Alzheimer’s type.
Study Population
Number of Patients: Approximately 1,200 patients will be enrolled at approximately 250 centers 
globally.
Condition/Disease: Patients with agitation secondary to dementia of the Alzheimer’s type. The 
diagnosis of probable Alzheimer’s disease will be based on the ‘2011 Diagnostic Guidelines for 
Alzheimer’s Disease’ issued by the National Institute on Aging (NIA)-Alzheimer’s Association 
(AA) workgroups.1 Diagnosis of agitation will be based on the provisional consensus definition 
of agitation in patients with cognitive disorders developed by the International Psychogeriatric 
Association (IPA) Agitation Definition Work Group.2 
Key Inclusion Criteria: Patient has successfully completed Studies 15-AVP-786-301, 
15-AVP-786-302, 12-AVR-131, or 17-AVP-786-305. Patients may be eligible to delay 
enrollment (which may include delays associated with coronavirus disease 2019 [COVID-19] 
restrictions) after receiving Medical Monitor approval, completing the defined screening 
assessments, and meeting the eligibility criteria. Eligible patients must have a reliable caregiver 
who is able and willing to comply with all required study procedures, including not 
administering any prohibited medications during the course of the study. 
Key Exclusion Criteria: Patient is currently participating in, or has participated in other 
interventional (drug or device) clinical study since exiting Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305 or within 30 days prior to Baseline for patients who 
delay enrollment. Patients with co-existent, clinically significant, or unstable systemic diseases 
that could confound the interpretation of the safety results of the study.
A complete list of inclusion/exclusion criteria is presented in Section 4 of the study protocol.
Study Design
Structure: This is a Phase 3, multicenter, long-term, extension study of the Phase 3 
Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305 which also allowed patients 
from the Phase 2 Study 12-AVR-131 to be included. Patients from Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305 should enroll in the current study within 5 days of the 
last visit (Visit 6, Day 85) in the preceding study. If enrollment from one of the preceding studies 
is delayed beyond 5 days, then only patients with Medical Monitor approval will be permitted to 
undergo screening and assessment for eligibility. Although all patients enrolled will receive 
AVP-786, the treatment dose assigned will be masked to the patient, investigator, study staff, and 
the sponsor. 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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CONFIDENTIAL AND PROPRIETARY
Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 11
Duration: Patients will be enrolled in the study for approximately 64 weeks. Patients who with 
Medical Monitor approval delay enrollment will have a screening period of up to 4-weeks. 
End of Trial: The end of trial is defined as the “Last Patient Last Visit”; which is the date on 
which the last patient has his or her last visit or assessment (either for therapeutic or follow-up 
purposes including a follow-up phone call).
Study Treatment: The investigational product is AVP-786 (deuterated [d6]-dextromethorphan 
hydrobromide [d6-DM; INN: deudextromethorphan]/quinidine sulfate [Q]). Three doses of 
AVP-786 will be used in the study; d6-DM 18 mg/Q 4.9 mg, d6-DM 28 mg/Q 4.9 mg and 
d6-DM 42.63 mg/Q 4.9 mg, hereafter referred to as AVP-786-18/4.9, AVP-786-28/4.9, and 
AVP-786-42.63/4.9, respectively. 
Control: None
Treatment Assignment: Eligible patients will be assigned to receive either AVP-786-42.63/4.9, 
AVP-786-28/4.9, or AVP-786-18/4.9 capsules in a masked manner, depending on the last 
treatment received in the preceding study (15-AVP-786-301, 15-AVP-786-302, and 
17-AVP-786-305). Study medication will be allocated via an interactive web response system 
(IWRS). 

Patients who received placebo in the preceding studies and patients who with Medical 
Monitor approval delay enrollment will be started on AVP-786-28/4.9 in the current 
study and titrated to the AVP-786-42.63/4.9 dose. 

Patients enrolling directly into 15-AVP-786-303 who received AVP-786-18/4.9 
previously will continue to receive AVP-786-18/4.9, patients who received 
AVP-786-28/4.9 will continue to receive AVP-786-28/4.9 and patients who received 
AVP-786-42.63/4.9 will continue to receive AVP-786-42.63/4.9. 
Dose Regimen: Study medication will be administered orally twice daily (BID, 1 capsule in the 
morning and 1 capsule in the evening approximately 12 hours apart) throughout the study. 
Patients who received placebo in the preceding studies and patients who delay enrollment will 
start with AVP-786-28/4.9 once a day for the first 7 days of the study, continue with 
AVP-786-28/4.9 BID for the next 14 days and from Day 22 (Week 3; between Visit 2 and 
Visit 2.1) onwards will receive AVP-786-42.63/4.9 BID unless the dose is adjusted (after 
Day 22). 
At the discretion of the investigator, the dose of study medication can be adjusted after Day 22 at 
any time during the study for safety or efficacy reasons. See Section 5.3.3 for details on dose 
adjustment during the study. 
Assessments and Visits 
There are up to 15 scheduled clinic visits in the study. Patients will attend clinic visits at 
Screening (Day -28 to Day -1, only for patients who delay enrollment), Baseline (Day 1), and on 
Days 15 (Visit 2; Week 2), 29 (Visit 2.1; Week 4), 43 (Visit 3; Week 6), 85 (Visit 4; Week 12), 
127 (Visit 4.1; Week 18), 169 (Visit 5; Week 24), 211 (Visit 5.1; Week 30), 253 (Visit 6; 
Week 36), 295 (Visit 6.1; Week 42), 337 (Visit 7; Week 48), 365 (Visit 8; Week 52), 
395 (Follow-up Visit 1; Week 56), and 455 (Follow-up Visit 2; Week 64). Patients who require 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Amendment 7, Version 8.0
OPDC
AVP-786
Page 12
dose-adjustments may have unscheduled visits for safety assessments at the discretion of the 
investigator. Study procedures will be performed at each visit as outlined in the Schedule of 
Evaluations and Visits (Table 1 and Table 2). 
Response Measures
Safety and Tolerability 
Safety and tolerability of AVP-786 will be assessed by reported adverse events (AEs), physical 
and neurological examinations, vital signs, clinical laboratory assessments, resting 12-lead 
electrocardiograms (ECGs), Sheehan Suicidality Tracking Scale (S-STS), Mini-Mental State 
Examination (MMSE), and the Epworth Sleepiness Scale (ESS).
Pregnancy tests will be conducted for patients of childbearing potential.
Efficacy 
Efficacy will be assessed using the Cohen-Mansfield Agitation Inventory (CMAI), 
Neuropsychiatric Inventory (NPI) agitation/aggression, irritability/lability, and aberrant  motor 
behavior domains, modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression 
of Change-Agitation (mADCS-CGIC-Agitation), Clinical Global Impression of Severity of 
Illness scale-Agitation (CGIS-Agitation), Patient Global Impression of Change (PGIC-rated by 
caregiver), Dementia Quality of Life (DEMQOL), Resource Utilization in Dementia (RUD) and 
EuroQol 5-Dimension 5-Level (EQ-5D-5L).
General Statistical Methods and Types of Analyses
Analysis Populations
The safety population which includes all patients who received study treatment will be used for 
all efficacy and safety data summaries. Four treatment groups will be presented for both safety 
and efficacy: AVP-786-42.63/4.9, AVP-786-28/4.9, AVP-786-18/4.9, and all patients combined. 
No treatment comparisons will be performed.
Safety Analyses
Safety and tolerability measures including reported AEs, vital signs, clinical laboratory 
assessments, resting 12-lead ECGs, S-STS, MMSE, and ESS will be summarized using 
descriptive statistics and/or frequency tables. 
Efficacy Analyses 
Summary statistics will be provided for observed efficacy data by visit. Observed raw value and 
change from baseline will be presented where applicable.
Sample Size Calculation
The sample size of approximately 1,200 patients enrolled will provide adequate study medication 
exposure to satisfy regulatory requirements. The assessment of mADCS-CGIC-Agitation, RUD, 
and DEMQOL will be performed with approximately 500 patients who completed prior to the 
implementation of Protocol Amendment 6.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Amendment 7, Version 8.0
OPDC
AVP-786
Page 13
Table 1
Schedule of Evaluations and Visits for Patients Enrolling Directly from Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305
Schedule of Evaluations and Visits for Patients Enrolling Directly from Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305
Visit:
Baseline1
Visit 22,
Visit 
2.12
Visit 32,
Visit 42,
Visit 
4.12
Visit 52
Visit 
5.12
Visit 62
Visit 
6.12
Visit 72
Visit 82/ 
ET3,4
Follow-
up Visit 
12,3,5
Follow-
up Visit 
22,6
Study Day:
Day 1 
Day 15
Day 29
Day 43
Day 85
Day 127 Day 169 Day 211 Day 253 Day 295 Day 337 Day 365 Day 395 Day 455
Procedure
End of Study 
Week
Week 2
Week 4
Week 6
Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 Week 52 Week 56 Week 64
Sign informed consent forms
X7
Medical history
X8
Risk assessment for falls 
(worksheet and TUG test9)
X8
Review of eligibility10
X8
Treatment assignment11
X
Physical and neurological 
exam
X8
X
Vital signs, height, and 
weight
X8
X
X
X
X
X
X12
X
X
X
X
X12
CGIS-Agitation
X8
X
X
X
X
mADCS-CGIC-Agitation13
X
X
X
X
X
ECG14
X14
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant: 
medications, nondrug 
therapies, and 
nonpharmacological 
interventions for agitation 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Amendment 7, Version 8.0
OPDC
AVP-786
Page 14
Schedule of Evaluations and Visits for Patients Enrolling Directly from Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305
Visit:
Baseline1
Visit 22,
Visit 
2.12
Visit 32,
Visit 42,
Visit 
4.12
Visit 52
Visit 
5.12
Visit 62
Visit 
6.12
Visit 72
Visit 82/ 
ET3,4
Follow-
up Visit 
12,3,5
Follow-
up Visit 
22,6
Study Day:
Day 1 
Day 15
Day 29
Day 43
Day 85
Day 127 Day 169 Day 211 Day 253 Day 295 Day 337 Day 365 Day 395 Day 455
Procedure
End of Study 
Week
Week 2
Week 4
Week 6
Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 Week 52 Week 56 Week 64
MMSE
X8
X
X
CMAI
X8
X
X
X
X
X
X
NPI agitation/aggression 
domain
X8
X
X
X
X
NPI irritability/lability and 
aberrant motor behavior 
domains
X8
X
X
CSDD9
X8
DEMQOL15
X8
X
X
EQ-5D-5L16
X8
X
X
PGIC17
X8
X
X
X
X
RUD18
X8
X
X
S-STS
X8
X
X
X
X
X
X
X
X
X
X
X
X
X
ESS19
X8
X
X
Administer morning dose of 
study medication20
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry, hematology, and 
urinalysis
X8
X
X
X21
X21
X21
X
X21
Urine pregnancy test22
X8
X
X
X
X
X
X
X
Dispense study drug and 
diary card
X
X
X
X
X
X
X
X
X
X
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 15
Schedule of Evaluations and Visits for Patients Enrolling Directly from Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305
Visit:
Baseline1
Visit 22,
Visit 
2.12
Visit 32,
Visit 42,
Visit 
4.12
Visit 52
Visit 
5.12
Visit 62
Visit 
6.12
Visit 72
Visit 82/ 
ET3,4
Follow-
up Visit 
12,3,5
Follow-
up Visit 
22,6
Study Day:
Day 1 
Day 15
Day 29
Day 43
Day 85
Day 127 Day 169 Day 211 Day 253 Day 295 Day 337 Day 365 Day 395 Day 455
Procedure
End of Study 
Week
Week 2
Week 4
Week 6
Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 Week 52 Week 56 Week 64
Review and return unused 
study medication and diary20
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; CGIS-Agitation = Clinical Global Impression of Severity of Illness scale for Agitation; CMAI = Cohen-Mansfield Agitation Inventory; 
CSDD = The Cornell Scale for Depression in Dementia; DEMQOL = Dementia Quality of Life scale; ECG = electrocardiogram; ET = early termination; EQ-
5D-5L = EuroQol 5-Dimension 5-Level; mADCS-CGIC-Agitation = modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change for 
Agitation; IWRS = interactive web response system; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; PGIC = Patient Global 
Impression of Change rated by the caregiver; RUD = Resource Utilization in Dementia; S-STS = Sheehan Suicidality Tracking Scale; TUG = Timed Up and Go 
test
1.
Baseline visit will occur within 5 days of patient’s exit from Studies 15-AVP-786-301, 15-AVP-786-302, or 17-AVP-786-305.
2.
Study Visits 2 (Day 15), 2.1 (Day 29), and 3 (Day 43) have a ± 3-day window. All other study visits have a ± 7-day window. 
3.
Early Termination Visit for patients who withdraw prior to study completion. Follow-up Visit 1 also applies to patients who withdraw prior to study 
completion (ET patients). See footnote 6 for Follow-up Visit 2.
4.
For patients who terminate early from the study, the patient/patient’s caregiver will be contacted by telephone for 5 consecutive days following ET Visit to 
query on the overall well-being of the patient. 
5.
An on-site follow-up visit (Follow-up Visit 1) will occur approximately 30 days after last dose of study medication for all patients including ET patients. 
6.
An on-site follow-up visit (Follow-up Visit 2) will occur approximately 3 months after last dose of study medication for all patients, including ET patients. 
7.
Informed consent can be obtained at the exit visit of Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305. 
8.
Patient data from the final visit (Visit 6) in the preceding studies will be used as Baseline for the current study, except for medical history which will be 
obtained from the Screening visit and MMSE which will be obtained from the Baseline visit from the preceding studies. Height should be collected at the 
Baseline visit only.
9.
The TUG test and CSDD should be performed at Baseline only for patients rolling over from Study 17-AVP-786-305.
10. For each patient from any study, the review of inclusion/exclusion criteria will be performed by the investigator.
11. Patients will be assigned to AVP-786-42.63/4.9, AVP-786-28/4.9 or AVP-786-18/4.9 through IWRS.
12. Weight should be measured at Visits 5 and 8 only.
13. Worksheet for mADCS-CGIC-Agitation from the Baseline visit in the preceding studies was to be considered as baseline information for assessing change at 
Visits 5 and 8 and is no longer required to be performed following the implementation of Protocol Amendment 6.
14. ECG should be performed predose and at least 1 hour after dosing at the Baseline visit. ECGs should be collected at any time during the other visits.
15. The DEMQOL is no longer required to be performed following the implementation of Protocol Amendment 6. The proxy version is to be rated by the 
caregiver, and the non-proxy version is to be rated only by patients with an MMSE score of ≥ 10 at Baseline. 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Amendment 7, Version 8.0
OPDC
AVP-786
Page 16
16. The EQ-5D-5L should be performed only for patients rolling over from Study 17-AVP-786-305.
17. PGIC is to be rated by the caregiver.
18. The RUD is no longer required to be performed following the implementation of Protocol Amendment 6.
19. The ESS is to be rated only by patients with an MMSE score of ≥ 10 at Baseline.
20. The first dose of study medication administered at the Baseline visit should be administered from the blister card in the clinic. All other study medication 
should be administered from the blister card by the caregiver, family member, nursing home staff, or self-administered with supervision. The time of 
administration should be recorded on the diary card. The blister card and diary card should be returned to the patient/caregiver at Visits 2 and 2.1 after 
reviewing for compliance.
21. Glycosylated hemoglobin (HbA1c) test should be performed at Visits 4, 5, 6, and 8.
22. Urine pregnancy test to be performed for patients of childbearing potential only (Section 6.2.5).
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Amendment 7, Version 8.0
OPDC
AVP-786
Page 17
Table 2
Schedule of Evaluations and Visits for Patients Who Delay Enrollment
Schedule of Evaluations and Visits for Patients Who Delay Enrollment 
Visit:
Screening1 Baseline Visit 22 Visit 2.12 Visit 32
Visit 42
Visit 4.12 Visit 52
Visit 5.12 Visit 62
Visit 6.12 Visit 72
Visit 82/ 
ET3,4
Follow-
up Visit 
12,3,5
Follow-
up Visit 
22,6
Study Day:
-28 to -1
Day 1
Day 15
Day 29
Day 43
Day 85
Day 127 Day 169 Day 211 Day 253 Day 295 Day 337 Day 365 Day 395 Day 455
Procedure
End of Study 
Week
Week 2 Week 4
Week 6 Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 Week 52 Week 56 Week 64
Sign informed consent 
forms
X
Medical history
X
Risk assessment for falls 
(worksheet and TUG test)
X
Review of eligibility7
X
X
Treatment assignment8
X
Physical and neurological 
exam
X
X
Vital signs, height, and 
weight
X
X9
X
X
X
X
X
X9
X
X
X
X
X9
CGIS-Agitation
X
X
X
X
X
X
mADCS-CGIC-
Agitation10
X
X
X
X
X
ECG11
X12
X13
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant: 
medications, nondrug 
therapies, and 
nonpharmacological 
interventions for agitation 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 18
Schedule of Evaluations and Visits for Patients Who Delay Enrollment 
Visit:
Screening1 Baseline Visit 22 Visit 2.12 Visit 32
Visit 42
Visit 4.12 Visit 52
Visit 5.12 Visit 62
Visit 6.12 Visit 72
Visit 82/ 
ET3,4
Follow-
up Visit 
12,3,5
Follow-
up Visit 
22,6
Study Day:
-28 to -1
Day 1
Day 15
Day 29
Day 43
Day 85
Day 127 Day 169 Day 211 Day 253 Day 295 Day 337 Day 365 Day 395 Day 455
Procedure
End of Study 
Week
Week 2 Week 4
Week 6 Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 Week 52 Week 56 Week 64
MMSE
X
X
X
X
CMAI
X
X
X
X
X
X
X
X
NPI agitation/aggression 
domain
X
X
X
X
X
X
NPI irritability/lability 
and aberrant motor 
behavior domains
X
X
X
CSDD
X
DEMQOL14
X
X
X
EQ-5D-5L
X
X
X
PGIC15
X
X
X
X
RUD16
X
X
X
S-STS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESS17
X
X
X
Administer morning dose 
of study medication18
X18
X
X
X
X
X
X
X
X
X
X
X
Chemistry, hematology, 
and urinalysis
X19
X19
X
X
X19
X19
X19
X
X19
Urine pregnancy test20
X
X
X
X
X
X
X
X
X
Dispense study drug and 
diary card
X
X
X
X
X
X
X
X
X
X
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
AVP-786
Page 19
Schedule of Evaluations and Visits for Patients Who Delay Enrollment 
Visit:
Screening1 Baseline Visit 22 Visit 2.12 Visit 32
Visit 42
Visit 4.12 Visit 52
Visit 5.12 Visit 62
Visit 6.12 Visit 72
Visit 82/ 
ET3,4
Follow-
up Visit 
12,3,5
Follow-
up Visit 
22,6
Study Day:
-28 to -1
Day 1
Day 15
Day 29
Day 43
Day 85
Day 127 Day 169 Day 211 Day 253 Day 295 Day 337 Day 365 Day 395 Day 455
Procedure
End of Study 
Week
Week 2 Week 4
Week 6 Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 Week 52 Week 56 Week 64
Review and return unused 
study medication and 
diary18
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; CGIS-Agitation = Clinical Global Impression of Severity of Illness scale for Agitation; CMAI = Cohen-Mansfield Agitation Inventory; 
CSDD = The Cornell Scale for Depression in Dementia; DEMQOL = Dementia Quality of Life scale; ECG = electrocardiogram; ET = early termination; 
mADCS-CGIC-Agitation = modified Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change for Agitation; IWRS = interactive web 
response system; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; PGIC = Patient Global Impression of Change rated by the 
caregiver; RUD = Resource Utilization in Dementia; S-STS = Sheehan Suicidality Tracking Scale; TUG = Timed Up and Go test.
1.
Screening visit is applicable only for patients who with Medical Monitor approval delay enrollment from 12-AVR-131 or 17-AVP-786-305. The Screening 
visit has a + 3-day window and may be extended after discussion with and approval by the Medical Monitor. 
2.
Study Visits 2 (Day 15) 2.1 (Day 29), and 3 (Day 43) have a ± 3-day window. All other study visits have a ± 7-day window. 
3.
Early Termination Visit for patients who withdraw prior to study completion. Follow-up visit 1 also applies to patients who withdraw prior to study 
completion (ET patients). See footnote 6 for Follow-up Visit 2.
4.
For patients who terminate early from the study, the patient/patient’s caregiver will be contacted by telephone for 5 consecutive days following early 
termination visit to query on the overall well-being of the patient. 
5.
An on-site follow-up visit (Follow-up Visit 1) will occur approximately 30 days after last dose of study medication for all patients including ET patients. 
6.
An on-site follow-up visit (Follow-up Visit 2) will occur approximately 3 months after last dose of study medication for all patients, including ET patients. 
7.
For each patient, a protocol eligibility form which includes the review of inclusion/exclusion criteria may be requested to be completed by the investigator.
8.
Patients will be assigned to study medication through IWRS.
9.
Weight should be measured at Baseline, and Visits 5 and 8 only. Height should be measured at the Baseline visit only.
10. The mADCS-CGIC-Agitation baseline evaluation worksheet was to be completed to record baseline information for assessing change at Visits 5 and 8 and is 
no longer required to be performed following the implementation of Protocol Amendment 6.
11. ECG at the Baseline visit should be performed predose and at least 1 hour after dosing.
12. ECG should be performed in triplicate at the Screening visit.
13. ECG should be performed at any time during the visits after the Baseline visit.
14. The DEMQOL is no longer required to be performed following the implementation of Protocol Amendment 6. The proxy version is to be rated by the 
caregiver. The non-proxy version is to be rated only by patients with an MMSE score of ≥ 10 at Baseline.
15. PGIC is to be rated by the caregiver.
16. The RUD is no longer required to be performed following the implementation of Protocol Amendment 6.
17. The ESS is to be rated only by patients with an MMSE score of ≥ 10 at Baseline.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Amendment 7, Version 8.0
OPDC
AVP-786
Page 20
18. The first dose of study medication administered at the Baseline visit should be administered from the blister card in the clinic. All other study medication 
should be administered from the blister card by the caregiver, family member, nursing home staff, or self-administered with supervision. The time of 
administration should be recorded on the diary card. The blister card and diary card should be returned to the patient/caregiver at Visits 2 and 2.1 after 
reviewing for compliance.
19. Thyroid function tests (TSH, and reflex T3 and T4 if TSH is abnormal) should be performed at the Screening visit only. Glycosylated hemoglobin (HbA1c) 
test should be performed at Screening, Baseline, and Visits 4, 5, 6, and 8.
20. Urine pregnancy test to be performed for patients of childbearing potential only (Section 6.2.5).
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Amendment 7, Version 8.0
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AVP-786
Page 21
1.
BACKGROUND AND CLINICAL RATIONALE
Alzheimer’s disease (AD), the most common form of dementia, is a progressive 
neurodegenerative disease eventually leading to death. An estimated 5.4 million Americans have 
Alzheimer’s disease, this number has doubled since 1980 and is expected to be as high as 
16 million by 2050.3 Among US adults over age 65, prevalence estimates of dementia range 
from 5% to 15%, with AD being the most common type of dementia.4–6 In the United Kingdom 
(UK), approximately 850,000 people suffer from dementia of which AD accounts for 
approximately 62% of the cases.7 
Agitation is widely recognized as a common and important clinical feature of AD and other 
forms of dementia.8 Although readily recognized by clinicians and caregivers, a consensus 
definition of agitation in dementia was only recently developed by the International 
Psychogeriatric Association (IPA) Agitation Definition Working Group (ADWG) with the 
following criteria: “1) occurring in patients with a cognitive impairment or dementia syndrome; 
2) exhibiting behavior consistent with emotional distress; 3) manifesting excessive motor 
activity, verbal or physical aggression; and 4) evidencing behaviors that cause excess disability 
impairing relationships and/or daily activities and are not solely attributable to another disorder 
(psychiatric, medical or substance-related)”.2 Agitation and/or aggression are estimated to affect 
up to approximately 80% of patients with dementia9,10 with an increase in prevalence as the 
disease progresses. 
Agitation in patients with dementia is associated with increased functional disability,11 worse 
quality of life12 earlier institutionalization,13 increased caregiver burden,11 increased healthcare 
costs,14 shorter time to severe dementia15 and accelerated mortality.15 For these reasons, agitation 
and aggression are the neuropsychiatric symptoms most likely to require pharmacological 
intervention in Alzheimer’s patients.8 Currently there is no treatment approved in the United 
States (US) for the management of agitation in patients with AD. In some countries of the 
European Union (EU), risperidone is indicated for the short-term treatment (up to 6 weeks) of 
persistent aggression in patients with moderate to severe AD unresponsive to 
nonpharmacological approaches and when there is a risk of harm to self or others.16 Clinicians 
resort to off-label use of antipsychotics, sedatives/hypnotics, anxiolytics, and antidepressants in 
an attempt to control symptoms.17 Unfortunately, these treatments have limited utility given a 
modest efficacy that is offset by relatively poor adherence, safety and tolerability.8,18,19 Thus a 
critical need exists to develop a safe and effective pharmacological intervention for the treatment 
of agitation in dementia. Such a treatment could profoundly impact patient care, reduce caregiver 
burden and potentially improve overall disease prognosis.
AVP-786 is a combination product of deudextromethorphan hydrobromide (d6-DM), a central 
nervous system (CNS)-active agent, and quinidine sulfate (Q), used as an inhibitor of d6-DM 
metabolism via the cytochrome P450 (CYP) liver isoenzyme 2D6 (CYP2D6). AVP-786 is being 
developed by Otsuka Pharmaceutical Development & Commercialization, Inc (OPDC, or 
Sponsor) for the treatment of neuropsychiatric conditions.
The receptor pharmacology of d6-DM supports a potential clinical benefit for agitation in 
patients with dementia of the Alzheimer’s type. d6-DM binds to receptors responsible for 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 15-AVP-786-303
Amendment 7, Version 8.0
OPDC
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Page 22
modulation of glutamate and monoamines, and also binds to the sigma-1 receptor; these 
interactions may be key to CNS therapeutics. Pharmacology studies conducted by the Sponsor 
with d6-DM have demonstrated that deuteration does not alter the basic pharmacology of DM. 
Pharmacokinetic (PK) and drug metabolism studies indicate that d6-DM is metabolized by the 
same metabolic pathways as DM, but that deuteration results in a decreased rate of metabolism 
by CYP2D6. 
Studies conducted by the Sponsor have shown that d6-deuterium modification of 
dextromethorphan reduces the rate of its CYP2D6 metabolism such that a low dose of quinidine 
was sufficient to achieve pharmacologically relevant plasma concentrations of d6-DM. The low 
levels of Q in AVP-786 may minimize the risk of interactions with other CYP2D6 substrates, 
limit Q levels even in the presence of CYP3A4 inhibitors, and minimize the risk of effects on 
cardiac repolarization and QTc interval. 
The clinical development program for AVP-786 includes 5 Phase 3 studies, patients from 3 of 
these Phase 3 studies (15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305) that evaluate 
the safety and efficacy of AVP-786 in patients with dementia of the Alzheimer’s type are eligible 
for enrollment into Study 15-AVP-786-303. Study 15-AVP-786-301 was a multicenter, 
randomized, double-blind, placebo-controlled study, with 12-week duration of treatment. 
Approximately 380 patients were planned to be enrolled in the study. Eligible patients were 
randomized to receive either AVP-786 or matching placebo capsules. Study 15-AVP-786-302 
was a multicenter, randomized, double-blind, placebo-controlled study with 12-week duration of 
treatment. Approximately 470 patients were planned to be enrolled in the study. Eligible patients 
were randomized to receive either AVP-786 or matching placebo capsules. 
Study 17-AVP-786-305 is currently ongoing and is also a multicenter, randomized, double-blind, 
placebo-controlled study with 12-week duration of treatment. Approximately 550 patients are 
planned to be enrolled in the study. Eligible patients will be randomized to receive either 
AVP-786 or matching placebo capsules.
The current study (Study 15-AVP-786-303) is an extension of the three Phase 3 Studies, 
15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305 to evaluate the long-term safety, 
tolerability and maintenance of efficacy of AVP-786 for the treatment of agitation in patients 
with dementia of the Alzheimer’s type. Patients who were enrolled in Study 12-AVR-131 have 
been allowed to enroll in the current study provided they meet study criteria, as they represent 
the study population of interest. The doses of AVP-786 evaluated in Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305 (AVP-786-42.63/4.9, AVP-786-28/4.9 and 
AVP-786-18/4.9) will continue to be used in the current study. Patients who, with Medical 
Monitor approval, delay enrollment into Study 15-AVP-786-303 following completion of the 
preceding study will start at a dose of AVP-786-28/4.9 BID and titrate up to AVP-786-42.63/4.9 
BID. The rationale for the 64-week duration of this study is based on the need to collect long-
term safety information on AVP-786 and to meet regulatory requirements for population 
exposure required to assess clinical safety.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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2.
STUDY OBJECTIVES
The objectives of the study are to evaluate the long-term safety and maintenance of efficacy of 
AVP-786 for the treatment of agitation in patients with dementia of the Alzheimer’s type.  
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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3.
STUDY DESIGN
This is a Phase 3, multicenter, long-term, extension study of the Phase 3 
Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305 of approximately 64 weeks 
in duration with an additional screening period of up to 4-weeks for patients who, with Medical 
Monitor approval, have delayed enrollment from a preceding study (may include delays 
associated with coronavirus disease 2019 [COVID-19] restrictions). Approximately 1,200 
patients will be enrolled at approximately 250 centers globally. There are up to 15 scheduled 
clinic visits in the study including Screening (Day -28 to Day -1, for patients who with Medical 
Monitor approval delay enrollment), Baseline (Day 1), and on Days 15 (Visit 2; Week 2), 29 
(Visit 2.1; Week 4), 43 (Visit 3; Week 6), 85 (Visit 4; Week 12), 127 (Visit 4.1; Week 18), 169 
(Visit 5; Week 24), 211 (Visit 5.1; Week 30), 253 (Visit 6; Week 36), 295 (Visit 6.1; Week 42), 
337 (Visit 7; Week 48), 365 (Visit 8; Week 52), 395 (Follow-up Visit 1; Week 56), and 455 
(Follow-up Visit 2; Week 64). 
Eligible patients will be assigned at the Baseline visit to receive AVP-786-42.63/4.9, 
AVP-786-28/4.9, or AVP-786-18/4.9 in a masked manner, depending on the last treatment 
received in the preceding study (15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305). 
Study medication will be administered orally twice daily throughout the study. Patients (or 
caregivers) will self-administer study medication on all study days except on the specified 
clinic-visit days when patients will be administered their morning dose of study medication at the 
clinic in the presence of site personnel, regardless of the time of day. Study medication will be 
allocated via an interactive web response system (IWRS) and assigned to patients as follows: 

Patients who received placebo in the preceding studies and patients who with Medical 
Monitor approval delay enrollment will be started on AVP-786-28/4.9 in the current 
study and titrated to the AVP-786-42.63/4.9 dose. 

Patients enrolling directly into 15-AVP-786-303 who received AVP-786-18/4.9 
previously will continue to receive AVP-786-18/4.9, patients who received 
AVP-786-28/4.9 will continue to receive AVP-786-28/4.9 and patients who received 
AVP-786-42.63/4.9 will continue to receive AVP-786-42.63/4.9.
Patients who received placebo in the preceding studies and patients who delay enrollment will 
start with AVP-786-28/4.9 once a day for the first 7 days of the study, continue with 
AVP-786-28/4.9 BID for the next 14 days and from Day 22 (Week 3; between Visit 2 and 
Visit 2.1) onwards will receive AVP-786-42.63/4.9 BID unless the dose is adjusted (after 
Day 22). 
At the discretion of the investigator, the dose of study medication can be adjusted after Day 22 at 
any time during the study for safety or efficacy reasons. Further details on dose adjustments 
during the study are presented in Section 5.3.3. 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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4.
STUDY POPULATION
The study population includes patients who have successfully completed 
Studies 15-AVP-786-301, 15-AVP-786-302, or 17-AVP-786-305 and are willing to participate 
in the current long-term extension study. 
In addition, patients from Study 12-AVR-131 who had a diagnosis of probable AD and presented 
with clinically meaningful, moderate/severe agitation secondary to AD have been allowed to 
enroll in the study. The diagnosis of probable AD will be based on the ‘2011 Diagnostic 
Guidelines for Alzheimer’s Disease’ issued by the National Institute on Aging 
(NIA)-Alzheimer’s Association (AA) workgroups.1 These new criteria were developed based on 
the review of the NINCDS-ADRDA criteria.20 Neither AD nor agitation should be explainable 
by delirium, substance use and/or major psychiatric disorders. The provisional consensus 
definition of agitation in patients with cognitive disorders developed by the Agitation Definition 
Work Group (ADWG) from the International Psychogeriatric Association (IPA),2 will be used 
for selecting study patients. This proposed definition is limited to patients with cognitive 
impairment and requires: (a) evidence of emotional distress; (b) one of 3 observable types of 
behaviors-excessive motor activity, verbal aggression, or physical aggression; (c) that the 
behavior causes excess disability; and (d) that the behaviors cannot be solely attributable to a 
suboptimal care environment or other disorder such as a psychiatric illness, a medical illness, or 
effects of a substance. 
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 have a caregiver that is able and willing to comply with all required study 
procedures, ensuring that the patient attends all study visits and takes the study medication as 
instructed. Caregivers will also be instructed to keep a study diary, to report any changes in 
patient’s status, including adverse events, standard of care setting (e.g., becoming a resident in an 
assisted living facility) and to provide their impression and assessment regarding the 
investigational treatment. In order to qualify as a reliable informant (i.e., caregiver) capable of 
assessing changes in the patient’s condition during this study, the individual must spend a 
minimum of 2 hours per day for 4 days per week with the study patient. 
4.1.
Inclusion Criteria
1. Patient has successfully completed Studies 15-AVP-786-301, 15-AVP-786-302, 
17-AVP-786-305, or 12-AVR-131 and is deemed eligible for enrollment by the 
investigator after review of the inclusion/exclusion criteria. (Note: A delay in enrollment 
from a prior study requires Medical Monitor approval and may include delays associated 
with COVID-19 restrictions.)
2. Males and females; patients who delay enrollment must be 50 to 90 years of age, 
inclusive.
3. Patients with a diagnosis of probable AD according to the 2011 NIA-AA working group 
criteria and must be either out-patients or residents of an assisted-living facility or a 
skilled nursing home.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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4. For patients who delay enrollment, they must have clinically significant, moderate/severe 
agitation at least 2 weeks prior to Baseline, that interferes with daily routine and for 
which a prescription medication is indicated, in the opinion of the investigator.
5. For patients who delay enrollment, they must have a diagnosis of agitation that meets the 
IPA provisional definition of agitation.
6. For patients who delay enrollment, they must have a CGIS-Agitation score of ≥ 4 
(moderately ill) at Screening and Baseline.
7. For patients who delay enrollment, they must have a MMSE score between 6 and 26 
(inclusive) at Screening and Baseline.
8. Patient has stable cardiac, pulmonary, hepatic, and renal function.
9. For patients who delay enrollment, they must have an ECG (obtained at Screening and 
evaluated by a central ECG reader) with no clinically significant findings.
10. Patients of childbearing potential who are sexually active must use an effective method of 
birth control for at least 1 month prior to randomization, during participation in the study, 
and for at least 30 days after the last dose of study drug. The following should be taken 
into consideration:

Patients of childbearing potential must use 2 of the following precautions in order to 
minimize the risk of failure of 1 method of birth control: vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, birth control pills, birth control depot 
injection, birth control implant, or condom with spermicide or sponge with 
spermicide. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of exposure to 
study drug, or withdrawal are not acceptable methods of contraception.

Patients who are sterile (i.e., had an oophorectomy and/or hysterectomy), 
postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause) or practice true abstinence (when this method is in line 
with the preferred and usual lifestyle of the patient) are exempt from this requirement.

Patients who are lactating, pregnant, or plan to become pregnant are excluded.
11. For patients who delay enrollment, a stable dose for at least 3 months prior to Baseline of 
medications for the treatment of AD (e.g., donepezil, rivastigmine, galantamine, 
memantine) is allowed. During the study, the initiation of approved therapies for the 
treatment of AD and dose adjustments are allowed for all patients.
12. For patients who delay enrollment, who have been on concomitant antidepressants such 
as selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, sertraline, citalopram) 
and serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine, 
desvenlafaxine, duloxetine), they are allowed provided the dose has been stable for at 
least 3 months prior to Baseline and within the package insert guidance for that 
medication. During the study, initiation of new drugs for depression, and dose 
adjustments are allowed for all patients. Paroxetine, a CYP2D6 substrate, is allowed 
provided the dose does not exceed 10 mg/day. 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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13. For patients who delay enrollment, who have been on concomitant hypnotics at bedtime 
(e.g., eszopiclone, zolpidem, zaleplon, trazodone [up to 50 mg/day]) for the nighttime 
treatment of insomnia, they are allowed, provided their dose has been stable for at least 
1 month prior to Baseline. During the study, initiation of new drugs for insomnia, and 
dose adjustments are allowed for all patients.
14. For patients who delay enrollment currently taking allowed medications for the treatment 
of agitation secondary to AD (e.g., atypical antipsychotics, antidepressants, buspirone) 
are eligible provided the dose has been stable for at least 1 month prior to Baseline 
(3 months prior for antidepressants). Dose adjustments are allowed during the study. 
Initiation of new drugs for the treatment of agitation are not allowed for all patients.
15. For patients who delay enrollment, they must not show current and significant symptoms 
of a depressive disorder and must have a score <10 in the Cornell Scale for Depression in 
Dementia (CSDD) at Screening. Patients rolling over from Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305 with scores greater than 10 in the CSDD at 
baseline should be evaluated by the investigator for enrollment in the current study. 
16. For patients who delay enrollment, they must have no history or current clinical 
symptoms of schizophrenia, schizoaffective disorder, or bipolar disorder, as defined in 
the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision 
(DSM-IV-TR).
17. Caregiver must be willing and able to comply with study procedures, including not 
administering any prohibited medications during the course of the study.
18. Patient/caregiver must be willing to sign and receive a copy of patient/caregiver informed 
consent form (ICF) after the nature and risks of study participation have been fully 
explained. Patients who are not capable of signing the ICF but are able to provide assent, 
or the patient’s authorized representative (as determined by local regulations) agrees to 
participation (for patients unable to provide assent) are allowed.
4.2.
Exclusion Criteria
1. Patient is currently participating in, or has participated in other interventional (drug or 
device) clinical study since exiting Studies 15-AVP-786-301, 15-AVP-786-302, and 
17-AVP-786-305, or within 30 days prior to baseline for patients who delay enrollment. 
2. Caregiver is unwilling or unable, in the opinion of the investigator, to comply with study 
instructions. 
3. Patients with co-existent clinically significant or unstable systemic diseases that could 
confound the interpretation of the safety results of the study (e.g., malignancy [except 
skin basal-cell carcinoma], poorly controlled diabetes, poorly controlled hypertension, 
unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated 
cardiomyopathy, or unstable valvular heart disease). Certain other non-metastatic cancer 
may be allowed. For patients who delay enrollment, each case to be evaluated 
individually with the Medical Monitor (MM). 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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4. Patients determined to have a high imminent risk of falls during the study based on a 
clinical evaluation by the investigator
5. For patients who delay enrollment, any personal history of complete heart block, QTc 
prolongation, or torsades de pointes, 
a.
Screening and Baseline QT interval corrected for heart rate using the Fridericia’s 
formula (QTcF) of > 450 msec for males and > 470 msec for females unless due to 
ventricular pacing (Screening ECG will be based on central review). Baseline predose 
ECG will be based on the machine read and investigator’s evaluation. If the Baseline 
predose ECG QTcF result from the machine read is exclusionary, the patient should 
not be dosed and the Medical Monitor should be contacted.
b. Presence of premature ventricular contractions (PVCs) as evaluated by a central 
reader and deemed clinically significant by the investigator. 
6. Patients who are currently using or were on NUEDEXTA® in the 2 weeks preceding 
Baseline.
7. Patients with evidence of serious risk of suicide at Screening (patients who delay 
enrollment) and Baseline based on the Sheehan Suicidality Tracking Scale (S-STS), i.e., a 
score of 3 or 4 on any one question 2 through 6 or 11 or a score of 2 or higher on any one 
questions 1a, 7 through 10, or 12, or who, in the opinion of the investigator, present a 
serious risk of suicide.
8. Patients who, in the opinion of the Investigator, Medical Monitor, or sponsor, should not 
participate in the study.
4.3.
Patient Withdrawal From the Study
Patients and caregivers will be advised verbally and in the written 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. The investigator or sponsor may discontinue a patient from the study in the 
event of an intercurrent illness, adverse event, 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. As the study design does not include a specific rescue treatment, based 
on their medical judgment and a risk/benefit assessment, the Investigator may make a decision 
about the appropriateness of continuation of the patient in the study. In case of significantly 
increased agitation and/or significant safety concerns in the judgment of the Investigator, the 
patient should be withdrawn from the study.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. Regardless of the circumstance, every effort should be made to document patient 
outcome, if possible. The investigator should inquire about the reason for withdrawal, request the 
caregiver return all unused investigational product (IP), and follow-up with the patient regarding 
any unresolved adverse events. 
In addition, patients who present with a persistent QTc interval (QTcF) > 500 msec (unless due 
to ventricular pacing) or a persistent QTcF interval change from the predose Baseline ECG of 
> 60 msec that is confirmed by the central ECG reader at any time after enrollment will be 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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withdrawn from the study. For patients enrolling directly from Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305, the post-dose ECG obtained at Visit 6 in the prior study 
will be used as the predose baseline for calculating change and for patients who delay 
enrollment, the predose ECG at the Baseline visit will be used. The QTcF values will be assessed 
for clinical significance and recorded.
Patients who withdraw prior to study completion will be asked to return to the clinic to complete 
the Visit 8 (end of study) assessments and a follow-up visit, 30 days after last dose of study 
medication. For all patients who terminate early from the study, patient/patient’s caregiver will 
be contacted by telephone for 5 consecutive days following ET visit to query on the overall 
well-being of the patient. 
If the patient withdraws from the study, and consent is withdrawn by the caregiver and/or 
patient’s representative for disclosure of future information, no further evaluations should be 
performed, and no additional data should 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.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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5.
STUDY TREATMENTS
5.1.
Treatments Administered
5.1.1.
Description of Study Medications
Clinical study medication will be provided as hard, printed, opaque, blue, gelatin capsules 
(size 3). Each capsule of the study medication contains 1 of the following (except for the 
AVP-786 placebo capsules for Days 1 to 7 for patients requiring titration [refer to Section 3]):

42.63 mg of d6-DM and 4.9 mg of Q (USP, EP): AVP-786-42.63/4.9

28 mg of d6-DM and 4.9 mg of Q (USP, EP): AVP-786-28/4.9

18 mg of d6-DM and 4.9 mg of Q (USP, EP): AVP-786-18/4.9
Drug supplies will be provided to the site in individual, pre-labeled blister cards. 
All medication used in this study will be prepared, packaged, and labeled in accordance with 
Good Manufacturing Practice (GMP) guidelines, International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, and applicable laws and regulations.
5.1.2.
Composition of AVP-786
The qualitative and quantitative compositions of the 3 doses of the IP are listed in Table 3.
Table 3
Composition of Investigational Product
Ingredient (amounts in mg)
AVP-786-
42.63/4.9
AVP-786-
28/4.9
AVP-786-
18/4.9
Deudextromethorphan hydrobromide (*) 
42.63 (33)
28.00 (21.67)
18.00 (13.93)
Quinidine sulfate USP, EP (*)
4.9 (4.26)
4.9 (4.26)
4.9 (4.26)
Croscarmellose sodium NF



Microcrystalline cellulose NF



Colloidal silicone dioxide NF



Magnesium stearate NF



Size 3 Blue Opaque capsules



EP = European Pharmacopoeia; USP = United States Pharmacopoeia; NF = National Formulary
* Free base equivalent indicated in parenthesis 
 Indicates inclusion of the excipient.
5.1.3.
Packaging
The investigators will be supplied with pre-labeled, individually pre-packaged blister cards. Each 
panel of the blister card (1 week of study medication) consists of 2 rows of blister strips, one row 
for the morning dose and one row for the evening dose (Figure 1). Each blister card will contain 
3 panels, providing sufficient study medication for 3 weeks of treatment and an additional 3 days 
of supply (total of 48 capsules). 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Figure 1
Sample Configuration of Investigational Product Blister Card
5.1.4.
Labeling
All labels will contain protocol number, product name, blister card number, an investigational 
drug warning, and dosage 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 either a 
2-panel label or booklet label, with a detachable panel that will be removed and affixed to the 
study medication Dispensing Log page at the time of dispensing. 

The 2-panel label provides space on both panels of the card label to record patient 
number, visit week, and dispensing date.

The booklet label does not provide space to record patient number, visit week, and 
dispensing date. This information will need to be handwritten on the Dispensing Log.
All investigational product 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 to 30°C (59°F-86°F).
5.1.6.
Study Medication Administration
All patients will receive study medication according to the blister card numbers assigned by an 
IWRS randomization scheme. Designated staff at each site will dispense study medication. The 
first dose (on Day 1) will be administered at each site by designated staff. For all other days, 
study medication should be administered to the patient by the caregiver, family member, nursing 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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home staff, or self-administered with supervision. Patients and caregivers will be instructed that 
the patient should take the study medication orally with water approximately every 12 hours 
± 4 hours (morning and evening). The time the patient takes each dose of medication should be 
recorded in the diary card. 
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
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 on the form, sign and date it, and return 
the form to the sponsor or its representative. 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 the 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 eCRF. This eCRF will contain the following information: (i) patient 
number to whom the IP was dispensed; (ii) the date(s) and quantity of the IP dispensed to the 
patient; and (iii) the blister card material ID number assigned to the patient via IWRS. 
Additionally, the detachable panel of the two-panel label on each blister card will be removed 
and affixed to the study medication Dispensing Log page at the time of dispensing. Space is 
provided on both panels of the blister card label to record patient number, the visit week and 
dispensing date. 
5.2.3.
Unused Supplies
At the end of the study, all unused investigational supplies must be inventoried on the Drug 
Accountability Log and destroyed on site or 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.
Treatment Assignment
Patients directly enrolling from Studies 15-AVP-786-301, 15-AVP-786-302, and 
17-AVP-786-305 will maintain the 6-digit patient number assigned to them in the preceding 
studies. For patients from Study 12-AVR-131, a 6-digit patient number will be assigned where 
the first 3 digits consist of the center number. The last 3 digits will be assigned sequentially 
starting with 801. This 6-digit number is the main identifier for patients.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Patients who received placebo in the preceding studies and patients who delay enrollment will be 
started on AVP-786-28/4.9 in the current study and titrated to the AVP-786-42.63/4.9 dose. For 
patients directly enrolling from the preceding studies, those patients who received 
AVP-786-18/4.9 previously will continue to receive AVP-786-18/4.9, those patients who 
received AVP-786-28/4.9 previously will continue to receive AVP-786-28/4.9 and those patients 
who received AVP-786-42.63/4.9 will continue to receive AVP-786-42.63/4.9. See Section 5.3.3 
for details on dose adjustment during the study. 
5.3.2.
Blinding/Masking
Eligible patients will be assigned to three different dose levels of AVP-786 as the starting doses 
via an interactive web response system (IWRS) [refer to Section 3]. If in the investigator’s 
judgement, it becomes medically necessary to identify which treatment a patient has received, 
the blind can be broken by the investigator. If identification of the study treatment is required for 
emergency therapeutic measures, the investigator or designee can immediately obtain the current 
treatment assignment electronically through the IWRS. In any situation requiring un-blinding, 
ideally the investigator should contact the study Medical Monitor to discuss the unmasking of a 
patient. If this is not possible, the study Medical Monitor should be notified as soon as possible.
5.3.3.
Treatment Dose Adjustment
As indicated in Section 5.3.2 above, the sponsor, patients, caregivers, investigators, or other 
study personnel will not be aware of the patient’s treatment dose assignment at study entry. After 
Day 22, the dose can be adjusted anytime for safety or efficacy reasons at the discretion of the 
investigator. A patient can be discontinued from the study at any time for safety reasons, based 
on the investigator’s assessment. Patients will have an unscheduled visit if the dose is adjusted 
on a non-scheduled visit day. 
5.4.
Patient Compliance
Patients and caregivers will be instructed to bring any unused study medication and empty blister 
cards to the clinic at all visits (Visits 2 through 8 [Days 15, 29, 43, 85, 127, 169, 211, 253, 295, 
337, and 365]). For this study, compliance will be defined as when a patient takes at least 80% of 
their scheduled doses (compliance range 80-120%). Caregivers will be provided with diary cards 
and will be instructed to record daily the number of capsules taken and the time of 
administration. Diary cards will be reviewed for compliance and collected at Visits 3 through 8 
(Days 43, 85, 127, 169, 211, 253, 295, 337, and 365), or at the time of early study 
discontinuation. Patients should bring their Diary Card at Visit 2 (Day 15) and Visit 2.1 (Day 29) 
for compliance review; the Diary Card will be returned to the patient and collected at the next 
visit. 
5.5.
Concomitant Medications and Nondrug Therapies
Patients may not take any of the disallowed medications listed in Appendix 1 during the study or 
2 weeks or 5 half-lives, whichever is longer, prior to the start of dosing on Day 1. At each visit, 
caregivers will be queried as to whether or not the patient has taken any concomitant medications 
and, if so, the investigator will record the medications taken and the reasons for their use. 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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AVP-786 contains quinidine which is a P-glycoprotein inhibitor. Concomitant administration of 
quinidine with digoxin, a P-glycoprotein substrate, results in serum digoxin levels that may be as 
much as doubled. Plasma digoxin concentrations should be closely monitored in patients taking 
digoxin concomitantly and dose reduced, as necessary.
In cases of prodrugs whose actions are mediated by the CYP2D6-produced metabolites (for 
example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be 
mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the 
desired clinical benefits in the presence of AVP-786 due to quinidine-mediated inhibition of 
CYP2D6. Alternative treatment should be considered.
The conditions of use for allowed concomitant medications and nondrug therapies or prohibited 
medications do not apply between Visit 8/ET and the Follow-up visits. Any use of medications 
or nondrug therapies during this period will be at the discretion of the investigator. Patients 
should allow at least 14 days after stopping study medication before starting an MAOI.
5.5.1.
Allowed Concomitant Medications for the Treatment of AD, Agitation, 
Depression, Insomnia, and Behavioral Disturbances
Drugs for the treatment of AD (e.g., donepezil, rivastigmine, galantamine, memantine), are 
allowed when administered at a stable dose for at least 3 months prior to Baseline, the dose of 
these drugs should remain unchanged throughout the study, if possible. However, initiation of 
approved therapies for the treatment of AD, and dose adjustments are allowed during the study.
Concomitant use of antidepressants such as SSRIs (e.g., fluoxetine, sertraline, citalopram) and 
SNRIs (e.g., venlafaxine, desvenlafaxine, duloxetine) are allowed provided the dose has been 
stable for at least 3 months prior to Baseline and within the Package Insert guidance for that 
medication. During the study, initiation of new drugs for depression, and dose adjustments are 
allowed. Paroxetine, a CYP2D6 substrate, is allowed provided the dose does not exceed 10 
mg/day. Patients taking SSRIs or SNRIs concomitantly should be monitored for serotonin 
syndrome which includes altered mental status, hypertension, restlessness, myoclonus, 
hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.
Concomitant use of hypnotics at bedtime (e.g., eszopiclone, zolpidem, zaleplon, trazodone [up to 
50 mg/day]) for the nighttime treatment of insomnia is allowed, provided the dose has been 
stable for at least 1 month prior to Baseline. During the study, initiation of new drugs for 
insomnia and dose adjustments are allowed.
The use of drugs for the treatment of agitation secondary to AD (e.g., atypical antipsychotics, 
antidepressants, buspirone), provided the patient has been on a stable dose at least 1 month prior 
to Baseline (3 months for antidepressants). Dose adjustments are allowed during the study. 
Initiation of new drugs for the treatment of agitation are not allowed.
Initiation of new drugs for the treatment of agitation are not allowed. All benzodiazepines are 
disallowed (See Section 5.5.2).
Short-term use (e.g. 7 days or less) of cold medications containing dextromethorphan are 
allowed (Appendix 1).
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Due to differences in the commercial availability of allowed concomitant medications in the 
specific country, please contact the Medical Monitor to discuss any alternative medications not 
listed above. 
5.5.2.
Rescue Medication for the Symptoms of Agitation
No rescue medications are allowed. As the study design does not include a specific rescue 
treatment, in case a patient experiences significantly increased agitation, based on their medical 
judgment and a risk/benefit assessment, the Investigator may make a decision about the 
appropriateness of continuation of the patient in the study (Section 4.3).
5.5.3.
Prohibited Concomitant Medications
A list of examples of prohibited medications is provided in Appendix 1. 
Monoamine oxidase inhibitors (MAOI) are prohibited throughout the study. Patients should 
allow at least 14 days after stopping study medication before starting an MAOI.
5.5.4.
Nondrug Therapies
Information on any prior and concomitant nondrug therapies will be recorded.
5.5.5.
Nonpharmacological Interventions for the Treatment of Agitation
Information on any nonpharmacological interventions for the treatment of agitation that were 
used prior to enrollment or used concomitantly during the study will be collected.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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For patients directly enrolling from Studies 15-AVP-786-301 and 15-AVP-786-302, the CSDD 
assessment at the final visit (Visit 6) in the preceding studies will be considered as Baseline. The 
CSDD will be assessed at Screening (Day -28 to Day -1, for patients who delay enrollment) and 
Baseline (Day 1, for patients directly enrolling from Study 17-AVP-786-305).
6.2.
Safety
6.2.1.
Adverse Events
6.2.1.1.
Definitions
An AE is any untoward medical occurrence or unintended change (e.g. physical, psychological, 
or behavioral) from the time ICF is signed, including inter-current illness, whether considered 
related to treatment or not. An AE can therefore be any unfavorable and unintended sign 
(including any clinically significant 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 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 or 
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. It 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 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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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 
medications administered to the patient
6.2.1.2.
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 (one 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” are not always 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, but all pregnancies occurring during the 
study will be reported on the Pregnancy and Breastfeeding Exposure Form (PBEF). The site 
should follow-up each trimester with the patient/partner until the final outcome is known (i.e., 
normal delivery, abnormal delivery, spontaneous/voluntary/therapeutic abortion). Should a 
complication occur that meets the requirements for an AE or SAE, it must be reported within 
24 hours of awareness. Patients 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 awareness. 
A pregnancy report form must also be completed in the event that the partner of childbearing 
potential of a male patient in the study 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.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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visit (Visit 6) in the preceding studies will be considered as Baseline. The physical examination 
will include assessments of head, eyes, ears, nose, throat, lymph nodes, skin, extremities, 
respiratory, gastrointestinal, musculoskeletal, cardiovascular, and nervous systems. The 
neurological examination will include assessments of mental status, cranial nerves, motor 
system, reflexes, coordination, gait and station, and sensory system. The physical and 
neurological examinations should be performed by the same person each time, whenever 
possible. 
6.2.3.
Vital Signs
Orthostatic blood pressure (BP) and heart rate (HR) measurements will be obtained at all clinic 
visits except on Follow-up Visit 1 (Day 395) and Follow-up Visit 2 (Day 455). For patients 
directly enrolling from Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305, the 
assessment at the final visit (Visit 6) in the preceding studies will be considered as Baseline. 
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 1 to 3 minutes of standing. 
Respiratory rate (breaths/minute) and body temperature (ºF/ºC) will be assessed at all clinic 
visits. Weight should be recorded at Baseline (Day 1, for patients who delay enrollment), Visit 5 
(Day 169), and Visit 8 (Day 365). For patients directly enrolling from Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305, the respiratory rate, temperature and weight 
assessments at the final visit (Visit 6) in the preceding studies will be considered as Baseline. 
Height should be recorded at Baseline (Day 1) for all patients.
6.2.4.
Clinical Laboratory Tests
The following clinical laboratory assessments are to be performed at Screening (Day -28 to Day 
-1, for patients who delay enrollment), Baseline (Day 1, for patients who delay enrollment), 
Visit 2 (Day 15), Visit 3 (Day 43), Visit 4 (Day 85), Visit 5 (Day 169), Visit 6 (Day 253), Visit 7 
(Day 337), and Visit 8 (Day 365) unless specified otherwise. For patients directly enrolling from 
Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305, the assessment at the final 
visit (Visit 6) in the preceding studies will be considered as Baseline.

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, and total 
cholesterol)

Hematology (red blood cell [RBC] count, hemoglobin, hematocrit, white blood cell 
[WBC] count, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, 
platelet count, and morphology)
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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
Urinalysis (pH, specific gravity, protein, glucose, ketones, blood, leucocyte esterase, 
nitrates, and microscopic appearance)

Thyroid function tests (TSH, and reflex T3 and T4 if TSH is abnormal) at Screening 
visit only for patients enrolled who delay enrollment

Glycosylated hemoglobin (HbA1c) test at the Screening visit (for patients enrolled 
who delay enrollment), Baseline Visit (for patients enrolled who delay enrollment), 
and Visit 4 (Day 85), Visit 5 (Day 169), Visit 6 (Day 253), and Visit 8 (Day 365). 
Any patients with clinically significant abnormal laboratory test results may be required by the 
MM to have a repeat test 1 week later or earlier, if medically indicated. Clinically significant 
laboratory abnormalities may be a basis for exclusion from study entry.
6.2.5.
Pregnancy Tests
Urine pregnancy tests are to be performed for patients of childbearing potential at Screening 
(Day -28 to Day -1, for patients who delay enrollment), Baseline (Day 1, for patients who delay 
enrollment), Visit 2 (Day 15), Visit 3 (Day 43), Visit 4 (Day 85), Visit 5 (Day 169), Visit 6 
(Day 253), Visit 7 (Day 337), and Visit 8 (Day 365). For patients enrolling directly from 
Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305, the assessment at the final 
visit (Visit 6) in the preceding studies will be considered as Baseline.
All 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. 
Patients of childbearing potential who are sexually active, must use an effective method of birth 
control for at least 1 month prior to Baseline, during the course of the study, and for at least 
30 days after the last dose of study drug. The following should be taken into consideration:

Patients of childbearing potential must use 2 of the following precautions in order to 
minimize the risk of failure of 1 method of birth control: vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, birth control pills, birth control depot 
injection, birth control implant, or condom with spermicide or sponge with 
spermicide. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence for the duration of exposure to 
study drug, or withdrawal are not acceptable methods of contraception.

Patients who are sterile (i.e., had an oophorectomy and/or hysterectomy), 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause) or practice true abstinence (when this method is in line with the preferred and 
usual lifestyle of the patient) are exempt from this requirement.

Patients who are lactating, pregnant or plan to become pregnant are excluded.
6.2.6.
Electrocardiograms
A resting 12-lead ECG will be performed at the following visits for all patients: Baseline 
(Day 1), Visit 2 (Day 15), Visit 3 (Day 43), Visit 4 (Day 85), Visit 5 (Day 169), Visit 6 
(Day 253), Visit 7 (Day 337), and Visit 8 (Day 365). For patients who delay enrollment, ECGs 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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2 = moderate chance of dozing, and 3 = high chance of dozing. A total score of 0 to 9 is 
considered to be normal. 
The ESS will be assessed at Baseline (Day 1, for patients who delay enrollment), Visit 5 
(Day 169), and Visit 8 (Day 365) for patients with an MMSE score of ≥ 10 at baseline. For 
patients directly enrolling from Studies 15-AVP-786-301, 15-AVP-786-302, and 
17-AVP-786-305, the ESS assessment at the final visit (Visit 6) in the preceding studies will be 
considered as Baseline. 
6.3.
Efficacy
6.3.1.
Cohen-Mansfield Agitation Inventory (CMAI)
The CMAI is used to assess the frequency of manifestations of agitated behaviors in elderly 
persons. It consists of 29 agitated behaviors that are further categorized into distinct agitation 
syndromes, also known as CMAI factors of agitation.27 These distinct agitation syndromes 
include: aggressive behavior, physically non-aggressive behavior, and verbally agitated 
behavior.28 Scores for the 3 dimensions will be derived based on the factor structure described by 
Rabinowitz, et al, 2005;29 further details are provided in the SAP. Each of the 29 items is rated 
on a 7-point scale of frequency (1 = never, 2 = less than once a week but still occurring, 3 = once 
or twice a week, 4 = several times a week, 5 = once or twice a day, 6 = several times a day, 
7 = several times an hour). The ratings are based on the 2 weeks preceding assessment of CMAI. 
The CMAI (long-form version) will be assessed at Screening (Day -28 to Day -1, for patients 
who delay enrollment), Baseline (Day 1, for patients who delay enrollment), Visit 4 (Day 85), 
Visit 5 (Day 169), Visit 6 (Day 253), Visit 8 (Day 365), Follow-up Visit 1 (Day 395), and 
Follow-up Visit 2 (Day 455). For patients enrolling directly from Studies 15-AVP-786-301 and 
15-AVP-786-302, and 17-AVP-786-305 the CMAI assessment at the final visit (Visit 6) in the 
preceding studies will be considered as Baseline. 
6.3.2.
Neuropsychiatric Inventory (NPI) Agitation/Aggression, Irritability/Lability, 
and Aberrant Motor Behavior Domains
The NPI is a validated clinical instrument for evaluating psychopathology in a variety of disease 
settings, including dementia. The NPI is a retrospective caregiver-informant interview covering 
12 neuropsychiatric symptom domains: delusions, hallucinations, agitation/aggression, 
depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, 
irritability/lability, aberrant motor behavior, sleep and nighttime behavioral disorders, and 
appetite/eating disorders.30 Neuropsychiatric manifestations within a domain are collectively 
rated by the caregiver in terms of both frequency (1 to 4) and severity (1 to 3), yielding a 
composite symptom domain score (frequency x severity). Caregiver distress is rated for each 
positive neuropsychiatric symptom domain on a scale anchored by scores of 0 (not distressing at 
all) to 5 (extremely distressing). 
Three domains of the NPI will be assessed in this study including: agitation/aggression, 
irritability/lability and aberrant motor behavior domains. The NPI agitation/aggression domain 
will be administered to the patient’s caregiver at Screening (Day -28 to Day -1, for patients who 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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delay enrollment), Baseline (Day 1, for patients who delay enrollment), Visit 4 (Day 85), Visit 5 
(Day 169), Visit 6 (Day 253), and Visit 8 (Day 365). 
The NPI irritability/lability and aberrant motor behavior domains will be administered to the 
patient’s caregiver at Baseline (Day 1, for patients who delay enrollment), Visit 5 (Day 169), and 
Visit 8 (Day 365). For patients enrolling directly from Studies 15-AVP-786-301, 
15-AVP-786 302, and 17-AVP-786-305, the assessments of the 3 domains of the NPI at the final 
visit (Visit 6) in the preceding studies will be considered as Baseline.
The NPI domains are generally evaluated for behaviors within the preceding 4 weeks but can be 
modified according to the needs of the study. In this study, the recall period will be 2 weeks for 
all the visits. 
The NPI nursing-home version (NPI-NH) will be used for patients from in-patient or assisted 
living facilities. The questions in the NPI-NH were rephrased for professional caregivers who 
may not know the patients prior to the onset of illness; however, the overall instrument domains 
and scoring is identical to the NPI except for the caregiver distress section which is replaced with 
occupational disruptiveness in the NPI-NH version. 
6.3.3.
Clinical Global Impression of Severity of Illness (CGIS-Agitation)
The CGIS is an observer-rated scale that measures illness severity and is one of the most widely 
used brief assessment tools in psychiatry research. 
The Early Clinical Drug Evaluation Unit (ECDEU) version of the CGIS is the most widely used 
format of this validated tool, and asks that the clinician rate the patient relative to their past 
experience with other patients with the same diagnosis, with or without collateral information. 
The CGIS has proved to be a robust measure of efficacy in many clinical drug trials31–35 and is 
easy and quick to administer, provided that the clinician knows the patient well.36 
Reliability and validity of CGI have been tested in multiple studies, including patients with 
dementia, schizophrenia and affective disorders. Overall, CGI showed high correlation (r: ~90%) 
with other assessment instruments and it has also shown positive significant relationships and 
concurrent validity with other clinician’s rating. In addition, the scale has good sensitivity to 
change over time.37–39 
The CGIS is a 7-point (1-7) scale (1 = normal, not at all ill; 7 = among the most extremely ill 
patients) and assesses severity of agitation in this study. The CGIS will be assessed at Screening 
(Day -28 to Day -1, for patients who delay enrollment), Baseline (Day 1, for patients who delay 
enrollment), Visit 4 ( Day 85), Visit 5 (Day 169), Visit 6 (Day 253), and Visit 8 (Day 365). For 
patients enrolling directly from Studies 15-AVP-786-301 and 15-AVP-786-302, and 
17-AVP-786-305, the CGIS-Agitation assessment at the final visit (Visit 6) in the preceding 
studies will be considered as Baseline.
6.3.4.
Modified Alzheimer’s Disease Cooperative Study - Clinical Global Impression of 
Change Rating (mADCS-CGIC-Agitation)
The assessment of mADCS-CGIC-Agitation will no longer be required to be performed 
following the implementation of Protocol Amendment 6.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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The standard ADCS-CGIC instrument was modified to better assess aspects relevant to studying 
agitation in AD (mADCS-CGIC-Agitation). The mADCS-CGIC-Agitation contains questions 
related to agitation and an assessment of the Clinician’s Impression of Change focused 
specifically on agitation. It was originally designed for the Citalopram study for Agitation in 
Alzheimer’s disease (CitAD)40,41 and utilizes a semi-structured interview of both patient and 
caregiver to determine a baseline level of severity for agitation. Subsequent evaluations assess 
for change from baseline and also utilize the semi-structured agitation interview of both patient 
and caregiver. 
The baseline mADCS-CGIC-Agitation evaluation will be conducted at the Baseline (Day 1) visit 
for patients who delay enrollment. The mADCS-CGIC-Agitation will be assessed at Visit 5 
(Day 169) and Visit 8 (Day 365) for change from baseline. The Baseline visit of preceding 
studies for patients enrolling directly from Studies 15-AVP-786-301, 15-AVP-786-302 and 
17-AVP-786-305 in agitation syndrome is the baseline for this study. The mADCS-CGIC-
Agitation will also be assessed at Follow-up Visit 1 (Day 395) and Follow-up Visit 2 (Day 455) 
for change from Visit 8/ET (Day 365).
6.3.5.
Patient Global Impression of Change (PGIC)
The PGIC is a 7-point (1-7) scale used to assess treatment response, and it is rated as: very much 
improved, much improved, minimally improved, no change, minimally worse, much worse, or 
very much worse.36 
The PGIC will be assessed and rated by the patient’s caregiver at Day 85 (Visit 4), Day 169 
(Visit 5), Day 253 (Visit 6), and Day 365 (Visit 8). 
6.3.6.
Dementia Quality of Life (DEMQOL)
The DEMQOL will no longer be required to be performed following the implementation of 
Protocol Amendment 6.
The DEMQOL is a scale used to evaluate health related quality of life in patients with dementia 
and their caregivers.42 There are 2 versions of the DEMQOL, a 28-item version (rated by patient) 
and a 31-item version (DEMQOL-proxy, rated by caregiver). Both the 28-item and 31-item 
version are recommended to be used for evaluating patients (and their caregivers) with mild to 
moderate dementia (MMSE ≥ 10). For patients with severe dementia, only the DEMQOL-proxy 
(administered to caregiver) is used. 
The DEMQOL-proxy (and DEMQOL for patients with MMSE ≥ 10 at baseline) will be assessed 
at Baseline (Day 1, for patients who delay enrollment), Visit 5 (Day 169), and Visit 8 (Day 365). 
For patients enrolling directly from Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-
786-305 the DEM-QOL-proxy (or DEMQOL) assessment at the final visit (Visit 6) in the 
preceding studies will be considered as Baseline.
6.3.7.
Resource Utilization in Dementia (RUD)
The RUD will no longer be required to be performed following the implementation of Protocol 
Amendment 6. 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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6.4.1.
Description of Study Procedures
At each visit throughout the study, site staff will be required to enter information into the IWRS 
regarding patient data and pre-defined study assessment results. Further instructions will be 
provided in the IWRS Site Manual.
6.4.1.1.
Screening Visit (Days -28 to -1, + 3-day window)
The Screening visit is applicable only to patients who with Medical Monitor approval delay 
enrollment. The following procedures will be performed (within 28 days prior to Day 1). The 
screening period may only be extended after discussion with and approval by the Medical 
Monitor. In the event that a patient is rescreened for enrollment, new informed consent and/or 
assent documents must be signed, new patient number assigned and all screening procedures 
repeated.
1. The investigator will provide the patients, authorized representatives and/or their 
caregivers with informed consent and/or assent documents and will explain the rationale 
for the study, providing ample time for participants, authorized representatives, and/or 
caregivers to ask questions.
2. Medical history, including patient demographics, any prior and concomitant medications 
use (including OTC, vitamins, and supplements), nondrug therapies, and any 
nonpharmacological interventions for the treatment of agitation will be reviewed and 
recorded.
3. Review inclusion/exclusion criteria (eligibility form may be requested to be completed).
4. Vital signs will be measured and recorded. 
5. Physical and neurological examination will be performed. 
6. Risk assessment for falls will be performed (worksheet and TUG test).
7. A resting 12-lead ECG will be performed in triplicate.
8. A blood and urine specimen will be collected for safety laboratory assessments. 
9. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
10. The following assessments will be completed:

MMSE; a score between 6 and 26 (inclusive) is required for study entry

CMAI

NPI Agitation/Aggression domain

CGIS-Agitation; a score of ≥ 4 is required for study entry

S-STS 

CSDD; a score of < 10 is required for study entry
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Following screening procedures for assessment of inclusion and exclusion criteria, the site may 
be requested to complete a Protocol Eligibility Form (PEF) and submit to the Medical Monitor 
for review and approval. Patients deemed eligible by the investigator and the Medical Monitor 
will be randomized into the study should they continue to qualify at the Baseline (Day 1) visit. 
Patients who have ECG or laboratory test results outside of the reference normal range that the 
investigator considers to be clinically significant, and may put the patient at a higher risk for 
study participation, will not be enrolled.
6.4.1.2.
Baseline Visit (Day 1)
The Baseline visit (Day 1) should occur in the morning, and should be within 5 days of exit from 
the preceding study for patients enrolling directly from Studies 15-AVP-786-301, 
15-AVP-786-302, and 17-AVP-786-305 or within 28 days after the Screening visit for those 
patients who delay enrollment. 
The following procedures will be performed. 
Before Dosing:
1. Informed consent and/or assent for patients enrolling directly from 
Studies 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305 will be obtained if it 
was not obtained at the final visit (Visit 6) in the preceding study. The investigator will 
provide the patients, authorized representative and/or their caregivers with informed 
consent and/or assent documents and will explain the rationale for the study, providing 
ample time for participants, authorized representatives, and/or caregivers to ask 
questions. 
2. Patient eligibility will be reviewed by the investigator for all patients (protocol eligibility 
form may be requested for patients who delay enrollment).
3. Caregivers will be queried regarding AEs, concomitant medication use (including OTC, 
vitamins, and supplements), nondrug therapies, and concomitant nonpharmacological 
interventions for treatment of agitation.
The following procedures performed before dosing are for patients who delay enrollment: 
1. Vital signs, height, and weight will be measured and recorded.
2. A resting predose 12-lead ECG will be performed. 
3. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
4. A blood and urine specimen will be collected for safety laboratory assessments. 
5. The following assessments will be completed:

MMSE

CMAI

NPI agitation/aggression, irritability/lability, and aberrant motor behavior domains

CGIS-Agitation
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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
S-STS

ESS (only for patients with an MMSE score of ≥ 10 at baseline)

EQ-5D-5L (only for patients who delay enrollment from 17-AVP-786-305)
The following procedures performed before dosing are for patients enrolling directly from 
Study 17-AVP-786-305:
1. Administer the following:

TUG test

CSDD
Study Medication Dosing:
Patients will be assigned with a study medication kit number via IWRS once it is determined that 
they satisfy all of the inclusion and none of the exclusion criteria. The first dose of study 
medication will be administered from the AM strip of blister card, at the clinic regardless of the 
time of day. 
After Dosing:
1. A resting postdose 12-lead ECG will be performed at least 1 hour after taking the 
morning dose of study medication.
2. The caregiver will be queried regarding AEs.
3. Patient Diary Card and sufficient study medication for a 3-week treatment period will be 
dispensed.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 14 days.
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication and patient’s Diary Card at each study visit. 
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
6.4.1.3.
Visit 2 (Day 15 ± 3-day window)
The Visit 2 (Day 15) dose of study medication can be administered at home, the time of dosing 
should be noted by the patient/caregiver. The following procedures will be performed at this 
visit:
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Amendment 7, Version 8.0
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1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
3. A resting 12-lead ECG will be performed.
4. A blood and urine specimen will be collected for safety laboratory assessments. 
5. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
6. Patient’s Diary Card will be collected, reviewed for compliance and returned to the 
patient.
7. The S-STS will be completed.
8. Unused study medication will be accounted for compliance and the blister card returned 
to the patient.
9. Sufficient study medication for a 3-week treatment period will be dispensed.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 14 days.
Patients/caregivers will be instructed to finish the study medication from the blister card returned 
to the patient before starting on the medication from the newly dispensed blister card. 
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.4.
Visit 2.1 (Day 29 ± 3-day window)
The Visit 2.1 (Day 29) dose of study medication can be administered at home, the time of dosing 
should be noted by the patient/caregiver. The following procedures will be performed at this 
visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Amendment 7, Version 8.0
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3. Patient’s Diary Card will be collected, reviewed for compliance and returned to the 
patient.
4. Unused study medication will be accounted for compliance and the blister card returned 
to the patient.
5. The S-STS will be completed.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 14 days.
Patients/caregivers will be instructed to finish the study medication from the blister card returned 
to the patient. 
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.5.
Visit 3 (Day 43 ± 3-day window)
The Visit 3 (Day 43) dose of study medication can be administered at home, the time of dosing 
should be noted by the patient/caregiver. The following procedures will be performed at this 
visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
3. A resting 12-lead ECG will be performed.
4. A blood and urine specimen will be collected for safety laboratory assessments. 
5. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
6. Patient’s Diary Card will be collected and reviewed for compliance.
7. Returned, unused study medication will be accounted for compliance.
8. The S-STS will be completed.
9. Patient Diary Card and sufficient study medication for a 6-week treatment period will be 
dispensed.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 42 days.
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.6.
Visit 4 (Day 85 ± 7-day window)
The Visit 4 (Day 85) dose of study medication can be administered at home, the time of dosing 
should be noted by the patient/caregiver. The following procedures will be performed at this 
visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
3. A resting 12-lead ECG will be performed.
4. A blood and urine specimen will be collected for safety laboratory assessments. 
5. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
6. Patient’s Diary Card will be collected and reviewed for compliance.
7. Returned, unused study medication will be accounted for compliance.
8. The following assessments will be completed:

CMAI

NPI Agitation/Aggression domain

CGIS-Agitation 

S-STS

PGIC
9. Patient Diary Card and sufficient study medication will be dispensed for a 6-week 
treatment period.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Amendment 7, Version 8.0
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Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 42 days.
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.7.
Visit 4.1 (Day 127 ± 7-day window)
The Visit 4.1 (Day 127) dose of study medication can be administered at home, the time of 
dosing should be noted by the patient/caregiver. The following procedures will be performed at 
this visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
3. Patient’s Diary Card will be collected and reviewed for compliance.
4. Unused study medication will be accounted for compliance. 
5. The S-STS will be completed.
6. Patient Diary Card and sufficient study medication will be dispensed for a 6-week 
treatment period.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 42 days.
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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requirements will be reviewed in person. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.9.
Visit 5.1 (Day 211 ± 7-day window)
The Visit 5.1 (Day 211) dose of study medication can be administered at home, the time of 
dosing should be noted by the patient/caregiver. The following procedures will be performed at 
this visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
3. Patient’s Diary Card will be collected reviewed for compliance.
4. Unused study medication will be accounted for compliance.
5. The S-STS will be completed.
6. Patient Diary Card and sufficient study medication will be dispensed for a 6-week 
treatment period.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 42 days. 
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.10.
Visit 6 (Day 253 ± 7-day window)
The Visit 6 (Day 253) dose of study medication can be administered at home, the time of dosing 
should be noted by the patient/caregiver. The following procedures will be performed at this 
visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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3. A resting 12-lead ECG will be performed.
4. A blood and urine specimen will be collected for safety laboratory assessments. 
5. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
6. Patient’s Diary Card will be collected and reviewed for compliance.
7. Returned, unused study medication will be accounted for compliance.
8. The following assessments will be completed:

CMAI

NPI Agitation/Aggression domain

CGIS-Agitation 

S-STS

PGIC
9. Patient Diary Card and sufficient study medication will be dispensed for a 6-week 
treatment period.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 42 days.
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.11.
Visit 6.1 (Day 295 ± 7-day window)
The Visit 6.1 (Day 295) dose of study medication can be administered at home, the time of 
dosing should be noted by the patient/caregiver. The following procedures will be performed at 
this visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Vital signs will be measured and recorded.
3. Patient’s Diary Card will be collected and reviewed for compliance.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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4. Unused study medication will be accounted for compliance.
5. The S-STS will be completed.
6. Patient Diary Card and sufficient study medication will be dispensed for a 6-week 
treatment period.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 42 days.
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.12.
Visit 7 (Day 337 ± 7-day window)
The Visit 7 (Day 337) dose of study medication can be administered at home, the time of dosing 
should be noted by the patient/caregiver. The following procedures will be performed at this 
visit:
1. Vital signs will be measured and recorded.
2. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
3. A resting 12-lead ECG will be performed.
4. A blood and urine specimen will be collected for safety laboratory assessments. 
5. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
6. Patient’s Diary Card will be collected and reviewed for compliance.
7. Returned, unused study medication will be accounted for compliance.
8. The S-STS will be completed.
9. Patient Diary Card and sufficient study medication will be dispensed for a 4-week 
treatment period.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study medication twice-daily 
(1 capsule of study medication from the top row [AM] of blister card in the morning and 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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1 capsule of study medication from the bottom row [PM] of the blister card in the evening, 
approximately every 12 hours ± 4 hours) for 28 days.
The investigator and/or study coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card. 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. Caregivers will also be instructed to bring to the clinic 
any unused study medication at each study visit. 
Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them.
6.4.1.13.
Visit 8 (Day 365 ± 7-day window) / Early Termination
Visit 8 (Day 365) should occur in the morning. Patients who withdraw prior to study completion 
are required to complete study procedures as listed in Visit 8 within 48 hours of the last dose of 
study medication. 
The following procedures will be performed:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. Returned, unused study medication will be accounted for compliance.
3. Patient’s Diary Card will be collected and reviewed for compliance.
4. Vital signs and weight will be measured and recorded.
5. Physical and neurological examination will be performed.
6. The following assessments will be completed:

MMSE

CMAI

NPI agitation/aggression, irritability/lability, and aberrant motor behavior domains

CGIS-Agitation

S-STS

PGIC

ESS (only for patients with an MMSE score of ≥ 10 at baseline)

EQ-5D-5L-proxy (and EQ-5D-5L for patients with an MMSE score of ≥ 10 at 
Baseline) only for Patients from Study 17-AVP-786-305
7. A resting 12-lead ECG will be performed.
8. A blood and urine specimen will be collected for safety laboratory assessments. 
9. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 6.2.5).
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Any previously reported and not yet resolved AE and any newly reported AE at the time of this 
visit will be followed-up for up to 30 days after the last dose of study medication.
6.4.1.14.
Follow-up Visit 1 (Day 395 ± 7-day window)
A follow-up visit will occur 30 days after the last dose of study medication for all patients 
including patients who terminate early from the study. 
The following procedures will be performed at this visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. The following assessments will be completed:

CMAI

S-STS
6.4.1.15.
Follow-up Visit 2 (Day 455 ± 7-day window)
A follow-up visit will occur approximately 3 months after the last dose of study medication for 
all patients, including patients who terminate early from the study.
The following procedures will be performed at this visit:
1. The caregiver will be queried regarding AEs, concomitant medication use (including 
OTC, vitamins, and supplements), nondrug therapies, and concomitant 
nonpharmacological interventions for treatment of agitation.
2. The following assessments will be completed:

CMAI

S-STS
6.4.1.16.
Follow-up Phone Call 
For patients who terminate early from the study, the patient/patient’s caregiver will be contacted 
by telephone for 5 consecutive days following ET visit to query on the overall well-being of the 
patient. 
6.4.1.17.
Unscheduled Visits
Patients will have an unscheduled clinic visit if the dose of study medication is adjusted. Dose 
adjustments can be made any time after Day 22. The safety assessments to be performed at the 
unscheduled visit will be based on clinical judgment of the investigator.
6.4.2.
End of Trial
The end of trial is defined as the “Last Patient Last Visit”; which is the date on which the last 
patient has his or her last visit or assessment (either for therapeutic or follow-up purposes 
including a follow-up phone call).
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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7.
DATA MANAGEMENT
7.1.
Data Collection
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 electronic data capture (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 data 
management plan 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 adverse events will be coded using a current version of Medical Dictionary 
for Regulatory Activities (MedDRA), and concomitant medications using a current version of 
the 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 at the sponsor’s site.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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8.
STATISTICAL METHODS
8.1.
Analysis Population
The safety population which includes all patients who received study treatment is the only 
analysis population that will be used in this study. It will be used for all efficacy and safety data 
summary. Four treatment groups will be presented for both efficacy and safety: 
AVP-786-42.63/4.9, AVP-786-28/4.9, AVP-786-18/4.9, and all patients combined. No treatment 
comparison will be performed.
8.2.
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized using descriptive statistics. 
8.3.
Safety Analysis
Safety and tolerability measures including reported AEs, vital signs, clinical laboratory 
assessments, resting 12-lead ECGs, S-STS, MMSE, and ESS will be summarized using 
descriptive statistics and/or frequency tables. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (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 (TEAE). TEAEs are those AEs that occur after the first dose of study 
medication up until 30 days after last dose. 
Summary statistics of absolute values and percentage change from baseline for BP (diastolic and 
systolic), heart rate, 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.
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. 
8.4.
Efficacy Analysis
Efficacy will be assessed using the CMAI, NPI (agitation/aggression, irritability/lability, and 
aberrant motor behavior domains), CGIS-Agitation, mADCS-CGIC-Agitation, PGIC, RUD, 
DEMQOL, and EQ-5D-5L. Summary statistics will be provided for observed efficacy data by 
visit. Observed raw value and change from baseline will be presented where applicable. The 
assessment of mADCS-CGIC-Agitation, RUD, and DEMQOL will be performed on subjects 
who enrolled prior to the implementation of Protocol Amendment 6.
8.5.
Interim Analysis
Interim analyses may be performed and will be pre-specified in the SAP.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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8.6.
Sample Size Calculations 
The sample size of approximately 1,200 patients enrolled will provide adequate study medication 
exposure to satisfy regulatory requirements. The assessment of mADCS-CGIC-Agitation, RUD, 
and DEMQOL will be performed with approximately 500 patients who completed prior to the 
implementation of Protocol Amendment 6.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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9.
ADMINISTRATIVE PROCEDURES
9.1.
Institutional Review Board/Ethics Committee Approval
Institutional Review Boards/Ethics Committees (IRBs/ECs) must meet the guidelines set out by 
the FDA and conform to local laws and customs where appropriate. Written IRB/EC approval 
for the protocol and the signed ICF must be obtained and transmitted to the Sponsor or 
representative before the study can be initiated. The IRB/EC must be informed of and approve all 
protocol amendments. The investigator will ensure that this study is conducted in full 
conformance with local laws and according to National and State/Provincial laws, GCP, ICH E6 
(r2) guidelines, and the World Medical Association Declaration of Helsinki.
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 (if the patient is capable in the judgment of the investigator to provide informed consent) 
or the authorized representative. For patients that are not capable of providing informed consent, 
but are capable of providing assent, the patient will be asked to provide assent. If the patient is 
not capable of providing assent, the investigator will document the reasons why and maintain 
that documentation with the other informed consent documents. The patient’s caregiver will also 
be asked to provide informed consent as they will be providing data on themselves and the 
patient, as well as, being responsible for ensuring compliance from the patient between study 
visits.
The patients and/or patient’s authorized representative and the caregiver will be properly 
informed of the purpose of the study. The patients and/or patient’s authorized representative and 
the caregiver will be alerted to any anticipated AE that may be encountered with the study 
medication. A signed ICF will be obtained from all patients and/or patient’s authorized 
representative and the caregiver prior to patient entry into this study. Patients and/or patient’s 
authorized representative and the caregiver will be provided with a copy of their signed and 
dated ICF.
9.3.
Patient’s Diary Card
The patient’s Diary Card will be reviewed by clinical study personnel at all study treatment visits 
for confirmation of medication dosage and any rescue medication received. The study personnel 
are responsible for (i) ensuring that patients and/or caregivers are properly collecting data and 
recording it into the diaries; and (ii) transcribing the diary recordings into the eCRF. The diary 
will be collected at all study visits after baseline except Visit 2 (Day 15), wherein the diary will 
be reviewed and returned to the patient. The originals of all diaries will be maintained at the site 
as source documents. 
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 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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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 electronic data capture (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.
9.5.
Quality Assurance
9.5.1.
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.
9.5.2.
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 and the caregiver for study procedures and for 
the release of medical records to the sponsor, FDA, other regulatory authorities, and the IRB/EC. 
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.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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9.6.
Record Retention
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient information 
to link records, e.g., CRFs 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 call 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 is unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), the Sponsor should be prospectively notified. The study 
records must be transferred to a designee acceptable by the Sponsor, such as another investigator, 
another institution, or to the Sponsor. The investigator must obtain the Sponsor’s written 
permission before disposing of any records, even if retention requirements have been met.
9.7.
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.
9.8.
Data Handling
Data collected on the eCRFs will be entered into EDC system by trained site staff. Any queries 
arising from data entry will be checked with the investigator and changes approved. 
9.9.
Laboratory Procedures
Each individual site laboratory will collect hematology and chemistry blood samples and urine 
samples for analysis. Instructions for specimen evaluation and transport to a central laboratory 
will be provided at the time of study initiation. 
9.10.
Guidelines for Good Clinical Practice
Standards for GCP and the ethical requirements equivalent to the provisions of Directive 
2001/20/EC (Clinical Trials Directive) must be adhered to for all study-based procedures.
9.11.
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 therapy, assessment variables, the number of patients 
treated, or patient selection criteria must be made only after appropriate consultation between an 
appropriate representative of the Sponsor and the investigator.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Protocol modifications must be prepared by a representative of the Sponsor or the investigator, 
and reviewed and approved by the Sponsor. 
All protocol modifications must be reviewed and approved by the appropriate IRB/EC 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/EC.
9.12.
Conditions for Terminating the Study
Both the Sponsor 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, the Sponsor and the 
investigator will assure that adequate consideration is given to the protection of the patient’s 
interests.
9.13.
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 the Sponsor, 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 the Sponsor, for example, patients’ signed ICFs, should be maintained by 
the investigator in strict confidence.
the Sponsor staff (or designee) will affirm and uphold the patient’s confidentiality. Throughout 
this study, all data forwarded to the Sponsor (or designee) will be identified only by the patient 
number assigned where applicable. 
9.14.
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 the United 
States Code of Federal Regulations (CFR) Title 21, Part 312.64.
9.15.
Publications
It is anticipated that a report of this study will be published in the scientific literature by the 
sponsor. The investigator will not seek to arrange for publication of any of the information or 
results from the study in any scientific journal, or other publication or by way of lecture without 
the Sponsor’s prior review and written consent. 
9.16.
Audits/Inspections
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel or designee(s) from the Sponsor or to health 
authority inspectors after appropriate notification. The verification of the eCRF data may be by 
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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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:

Visits from the sponsor’s representatives

IRB/EC approval(s)

Study medication accountability

Study protocol and amendments

ICFs of the patient (if capable of providing ICF, according to the investigator) or 
patient’s authorized representatives and caregivers

Assent of the patients (if capable of providing assent, according to the investigator)

Medical records supportive of eCRF data

Reports to the IRB/EC and the sponsor

Record retention
The sponsor will be available to help investigators prepare for an inspection.
Abbreviated Clinical Study Report 15-AVP-786-303
16.1.1 Protocol and Protocol Amendments
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Abbreviated Clinical Study Report 15-AVP-786-303
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Policy. 1990;16(3):199-208.
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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12.
APPENDICES
Appendix 1
Prohibited Concomitant Medications 
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APPENDIX 1.
PROHIBITED CONCOMITANT MEDICATIONS 
Patients who are currently taking, or have taken any of the following types of drugs, within 
2 weeks or 5 half-lives, whichever is longer, prior to the initiation of the study medication 
administration, are to be excluded. 
A. Certain drugs that may increase Q levels (exclusion does not include topical 
medications unless applied under occlusive dressing or other technique that is intended to 
increase systemic absorption): 

amiodarone

antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

carbonic anhydrase inhibitors (strong inhibitors are prohibited: topiramate is allowed) 

cimetidine 

delavirdine

diltiazem 

macrolide antibiotics (e.g., erythromycin, azithromycin, clarithromycin, 
telithromycin, dirithromycin, roxithromycin)

mexiletine

nefazodone

protease inhibitors (e.g., amprenavir, atazanavir, fosemprenavir, indinavir, ritonavir, 
saquinavir) 

ranolazine

verapamil 
B. Certain drugs that may have increased plasma levels if co-administered with Q: 

atomoxetine

tricyclic antidepressants (TCA; e.g., amitriptyline, amoxapine, clomipramine, 
desipramine, doxepin, imipramine, nortriptyline, protriptyline) 

pimavanserin
C. Drugs that are related to Q: 

mefloquine

quinidine

quinine 
D. Monoamine oxidase inhibitors (MAOIs) (may increase the risk of serotonin syndrome)
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Patients should allow at least 14 days after stopping study medication before starting an 
MAOI.
E. CYP3A4 inducers that may decrease DM or Q plasma levels: 

apalutamide

carbamazepine 

dexamethasone

enzalutamide

fosphenytoin

lumacaftor

mitotane

pentobarbital

phenobarbital 

phenytoin 

primidone

rifampicin

rifamycin

rifaximin

St. John’s wort 
F. Certain drugs that may be prescribed for the treatment of agitation or other 
indications, but prohibited from this study: 

benzodiazepines (e.g. lorazepam)

phenothiazines (e.g., chlorpromazine, fluphenazine, levomepromazine, 
methotrimeprazine, mesoridazine, pencyanzine, perphenazine, prochlorperazine, 
promazine, thioridazine, thiothixene, trifluoperazine, triflupromazine)

typical antipsychotics (e.g., droperidol, haloperidol, loxapine, molindone, pimozide, 
zuclopenthixol)

clozapine
G. Medications containing dextromethorphan are prohibited, except for intermittent, 
short-term use (e.g. 7 days or less) of cold medications containing dextromethorphan 
for the treatment of cold and flu symptoms.
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100