A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 (Deudextromethorphan 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.

Table of Contents
Table of Contents................................................................................................. 1
Study 20-avp-786-307 Protocol Amendment 2; 15 May 2023............................ 2
80
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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CONFIDENTIAL
OPDC
Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
1
PROTOCOL TITLE: 
A Phase 3, multicenter, randomized, double-blind, placebo-controlled study to assess the 
efficacy, safety, and tolerability of AVP-786 (deudextromethorphan hydrobromide 
[d6-DM]/quinidine sulfate [Q]) for the treatment of agitation in patients with dementia of 
the Alzheimer’s type
Protocol:
20-AVP-786-307 Amendment 2
EU CT No.: 2023-504991-31-00
                                                                                  EudraCT No.: 2020-000799-39
                                                                                                                IND: 124099
Sponsor:    Otsuka Pharmaceutical Development &
Date: 15 May 2023
 Commercialization, Inc.
Drug:
AVP-786 (deudextromethorphan
Version: 3.0
hydrobromide [d6-DM]/quinidine sulfate [Q])
Supersedes Version: 2.0
Immediately Reportable Event: 
Syneos Health
Otsuka Pharmaceutical Development & Commercialization, Inc.
2440 Research Blvd
Rockville, MD 20850  United States
Phone: 949-389-6700
Fax: 949-643-6891
CONFIDENTIALITY STATEMENT
This document contains confidential and proprietary information of Otsuka 
Pharmaceutical Development & Commercialization, Inc. (OPDC), and it is for the sole 
information and use of the investigator’s research team and the appointed Institutional 
Review Board/Independent Ethics Committee.
Abbreviated Clinical Study Report 20-AVP-786-307
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
OPDC
Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
2
PROTOCOL AGREEMENT
Protocol Title:
A Phase 3, multicenter, randomized, double-blind, placebo-controlled study to assess the 
efficacy, safety, and tolerability of AVP-786 (deudextromethorphan hydrobromide 
[d6-DM]/quinidine sulfate [Q]) for the treatment of agitation in patients with dementia of the 
Alzheimer’s type.
Protocol Number: 20-AVP-786-307 Amendment 2 (15 May 2023)
This document is a confidential communication of Pharmaceutical Development & 
Commercialization, Inc (OPDC). The recipient agrees that no unpublished information contained 
within this document or protocol will be disclosed or published without prior consent and written 
approval from OPDC. An exception to this agreement may be made for the purposes of ethical or 
regulatory review, in which case this document may be disclosed to an Ethics Review Board or 
any authorized representative of a national authority as required by regulation.
The signatures of the principal investigator and representative of the sponsor below constitute 
their approval of this protocol and further provide the necessary assurances that:
1. This study will be conducted according to Good Clinical Practice (GCP) and to all 
stipulations, as specified in both clinical and administrative sections of the protocol 
including the Declaration of Helsinki.
2. The conduct and results of this study will be kept confidential, and the electronic case 
report forms (eCRFs) and other pertinent data will become the property of OPDC 
Pharmaceuticals.
3. The protocol contains all necessary information required to conduct the study, as outlined 
in the protocol, and that the study will not be initiated without the approval of an 
appropriate Institutional Review Board/Independent Ethics Committee (IRB/IEC/EC).
4. All participants in this study will provide written informed consent in accordance with 
the requirements specified in the Code of Federal Regulations (21 CFR Parts 50, 56, 312) 
and/or the Declaration of Helsinki. All participants will also be informed that their 
medical records will be kept confidential except for review by OPDC or its 
representatives, the U.S. Food and Drug Administration (FDA), and other regulatory 
agencies.
Principal Investigator Signature
Date
Principal Investigator Name:
OPDC Representative Signature
Date
OPDC Representative: 
, MD
 Global Clinical Development
Abbreviated Clinical Study Report 20-AVP-786-307
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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PPD

CONFIDENTIAL
OPDC
Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
3
SYNOPSIS  
Name of Sponsor/Company:  Otsuka Pharmaceutical Development & Commercialization, Inc.
Name of Investigational Product:
AVP-786 (deudextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q])
Name of Active Ingredient(s):
deudextromethorphan hydrobromide [d6-DM] and quinidine sulfate [Q]
Protocol Number:
20-AVP-786-307
Phase: 3
Country: United States (US), 
Europe, other global sites
Title of Study: 
A Phase 3, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy, 
safety, and tolerability of AVP-786 (deudextromethorphan hydrobromide [d6-DM]/quinidine sulfate 
[Q]) for the treatment of agitation in patients with dementia of the Alzheimer’s type
Study Center(s): Approximately 110 global centers, including the US and Europe
Studied Period (years): 
Estimated date first patient enrolled: Sep 2020
Estimated date last patient completed: Dec 2024
Phase of development: 
3
Objectives: 
The primary objective is to:
•
Evaluate the efficacy, safety, and tolerability of AVP-786 compared to placebo for the 
treatment of agitation in patients with dementia of the Alzheimer’s type
The secondary objectives are to:
•
Evaluate the effects of AVP-786 compared to placebo on global assessments of severity and 
improvement of agitation
•
Evaluate the effects of AVP-786 compared to placebo on neuropsychiatric symptoms
•
Evaluate the effects of AVP-786 compared to placebo on measures of quality of life and 
resource utilization
Study Design: Phase 3, multicenter, randomized, double-blind, placebo-controlled study
Methodology: 
Screening Period (Days -28 to -1): A protocol eligibility form will be completed for each patient and 
reviewed by a Medical Monitor for approval prior to participation in the study.
12-week Double-blind Treatment Period (Days 1-85): All eligible patients will be randomly assigned 
to receive either AVP-786 or placebo (identical in appearance to AVP-786).
30-day Follow-up Period: All enrolled patients, whether they complete the study or terminate from 
the study early for any reason, will have a Follow-up visit 30 days after the last dose of study drug for 
select efficacy and safety assessments.
Assessments and Visits: Patients will attend clinic visits at Screening, Baseline (Day 1), 
Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 29), Visit 5 (Day 43), Visit 6 (Day 57), 
Visit 7 (Day 71), Visit 8/Early Termination (ET) (Day 85), and Follow-up (30 days after the last 
dose). 
Study procedures performed at each visit are outlined in the Schedule of Assessments (Table 1).
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
4
Number of Patients (planned): Approximately 750 patients 
Diagnosis and Main Criteria for Inclusion: Patients with agitation secondary to Alzheimer’s 
dementia; 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. 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.
Key Inclusion Criteria: Patients 50 to 90 years of age (inclusive) with clinically significant, 
moderate-to-severe agitation for at least 2 weeks prior to Screening that interferes with daily routine 
per the Investigator’s judgment, and who require pharmacotherapy for the treatment of agitation per 
the Investigator’s judgment after an evaluation of reversible factors and a course of 
nonpharmacological interventions. A Neuropsychiatric Inventory Agitation/Aggression (NPI-AA) 
score of ≥ 4 and Mini Mental State Examination (MMSE) score of 8 to 24 (inclusive) at Screening 
and Baseline are required for study participation. Patients must meet an additional predetermined 
blinded eligibility criterion, which will remain blinded to the clinical study site Investigators and staff. 
Eligible patients must have a reliable caregiver who is able and willing to comply with all study 
procedures, including adherence to administering study drug and not administering any prohibited 
medications during the course of the study, and who spends a minimum of 2 hours per day for 4 days 
per week with the patient.
Key Exclusion Criteria: Patients with dementia predominantly of the non-Alzheimer’s type (eg, 
vascular dementia, frontotemporal dementia, Parkinson’s disease, substance-induced dementia) and 
patients with symptoms of agitation that are not secondary to Alzheimer’s dementia (eg, secondary to 
pain, other psychiatric disorder, or delirium) are not eligible.
Investigational Product, Dosage and Mode of Administration: 
AVP-786 capsule will be administered orally BID up to a maximum dose of d6-DM 42.63 mg and Q 
4.9 mg.
Duration of Treatment: Patients will be enrolled in the study for approximately 20 weeks, which 
includes:
•
Up to a 28-day Screening Period
•
12-week Double-blind Treatment Period
•
30-day Follow-up Period
Reference Therapy, Dosage and Mode of Administration: 
Matching placebo capsule (identical appearance to AVP-786 capsule) will be administered orally 
BID.
Criteria for Evaluation:
Efficacy:
Primary Efficacy Measure: Cohen-Mansfield Agitation Inventory (CMAI)
Key Secondary Efficacy Measure: Clinical Global Impression of Severity of Illness for Agitation 
(CGIS-Agitation)
Other Efficacy Measures: Other efficacy measures include, Clinical Global Impression of Change 
(CGIC-Agitation), NPI-AA, NPI total, EuroQol 5-Dimension 5-Level (EQ-5D-5L), and Resource 
Utilization in Dementia-Lite (RUD-Lite). 
Abbreviated Clinical Study Report 20-AVP-786-307
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 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
5
Pharmacokinetics: Plasma concentrations of d6-DM, its metabolites d3-dextrorphan (d3-DX) and 
d3-3-methoxymorphinan (d3-3-MM), and Q will be measured. Urine concentrations of d6-DM and its 
metabolite d3-DX will be measured.
Safety: 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), MMSE, the Epworth Sleepiness Scale (ESS), and the Sheehan 
Suicidality Tracking Scale (S-STS).
Statistical Methods: Complete details of the planned statistical analysis will be presented in the 
Statistical Analysis Plan (SAP).
Efficacy Analyses: The primary efficacy endpoint is the change from Baseline to the end of the 
efficacy period in the CMAI total score.
All efficacy analyses will be based on the intent-to-treat analysis set, defined as all patients in the 
randomized population who take at least 1 dose of study drug (AVP-786 or placebo), have a Baseline, 
and at least 1 post-Baseline evaluation for the CMAI total score. Descriptive statistics will be 
provided for all efficacy variables in general. Continuous variables will be summarized by tabulations 
of mean, median, range, and standard deviation (SD). Tabulations of frequency distributions will be 
provided for categorical variables. The primary endpoint will be analyzed using mixed-effect model 
repeat measures (MMRM). The primary statistical comparison of interest is AVP-786 versus placebo. 
The null hypothesis of this comparison is that there is no difference between the AVP-786 treatment 
group and placebo in change from Baseline to the end of the efficacy period in the CMAI total score. 
This comparison will be tested for statistical significance at a 0.05 (2-sided) significance level. Details 
of sensitivity analyses under the assumption of missing not at random will be provided in the SAP.
Pharmacokinetic Analyses: Plasma concentrations of d6-DM, its metabolites d3-DX and d3-3-MM, 
and Q will be summarized descriptively. Urine concentrations of d6-DM and its metabolite d3-DX 
will be summarized descriptively.
Safety Analyses: Safety analyses will be based on safety population defined as all patients who are 
randomized and take at least one dose of study drug. It will consist of data summaries for biological 
parameters and AEs. Descriptive statistics will be provided for all safety variables in general. 
Continuous variables will be summarized by tabulations of mean, median, range, and SD. Tabulations 
of frequency distributions will be provided for categorical variables. Safety analyses will be tabulated 
by treatment. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summary statistics of absolute values and percentage change from baseline for blood pressure 
(systolic and diastolic), heart rate, respiratory rate, and ECG parameters will be provided. All values 
outside a predefined normal range will be highlighted in the individual patient data listings. 
Laboratory parameters will be summarized via descriptive statistics and via shifts in results with 
respect to normal ranges between Baseline and end of treatment as increased, decreased, or no 
change. The S-STS, MMSE, and ESS will be summarized via descriptive statistics.
Sample Size: Approximately 750 patients. Statistical assumptions and additional details are provided 
in the SAP.
Interim Analysis: An interim analysis may be performed and will be prespecified in the Interim 
Analysis Plan (IAP).
Abbreviated Clinical Study Report 20-AVP-786-307
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 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
6
Table 1:
Schedule of Assessments and Visits
12-WEEK DOUBLE-BLIND TREATMENT PERIOD
Visit:
Screeninga 
Baseline
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
(or ET)
Follow-up 
Visit b
Study Day:
Day
-28 to -1
Day 1
Day 8
(±3days)
Day 15
(±3days)
Day 29
(±3days)
Day 43
(±3days)
Day 57
(±3days)
Day 71
(±3days)
Day 85
(±3days)
30 (+7) days
Post Last 
Dose
Procedure
End of Study Week:
Week 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
ELIGIBILITY and HISTORY
Signed informed consent forms
X
Inclusion and exclusion criteria
X
X
Medical, psychiatric, and neurological history
X
Risk assessment for falls (worksheet and TUG)
X
Hachinski Ischemic Scale (Rosen Modification)
X
Protocol eligibility formc
X
EFFICACY
CMAI
X
X
X
X
X
X
X
X
X
X
CGIS-Agitation
X
X
X
X
X
X
X
X
X
X
CGIC-Agitation
X
X
X
X
X
X
X
NPId
Xd
X
X 
Xd
Xd
X 
Xd
X 
X 
EQ-5D-5L
X
X
RUD-Lite
X
X
SAFETY
Vitals signs
X
X
X
X
X
X
X
X
X
Weight and heighte
Xe
Xe 
Physical and neurological examination
X
X
ECG
Xf
Xg
Xg
Xh
Xh
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
7
12-WEEK DOUBLE-BLIND TREATMENT PERIOD
Visit:
Screeninga 
Baseline
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
(or ET)
Follow-up 
Visit b
Study Day:
Day
-28 to -1
Day 1
Day 8
(±3days)
Day 15
(±3days)
Day 29
(±3days)
Day 43
(±3days)
Day 57
(±3days)
Day 71
(±3days)
Day 85
(±3days)
30 (+7) days
Post Last 
Dose
Procedure
End of Study Week:
Week 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Chemistry, hematology, urinalysis
Xi
X
Xi
Urine pregnancy testj
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Prior and concomitant medications, non-drug 
therapies, nonpharmacological interventions for 
agitation
X
X
X
X
X
X
X
X
X
X
MMSE
X
X
X
ESSk
X
X
S-STS
X
X
X
OTHER PROCEDURES
PK blood samplel 
X
X
X
PK urine samplem
X
CYP2D6 blood sample
X
Amyloid β blood sample
X
Administer morning dose of study drug in 
clinic
X
X
X
Dispense blister card and diary cards
X
X
X
X
X
X
X
Review blister card and diary cards
X
X
X
X
X
X
X
AE = adverse event; CGIC-Agitation = Clinical Global Impression of Change for Agitation; CGIS-Agitation = Clinical Global Impression of Severity of Illness for Agitation; 
CMAI = Cohen-Mansfield Agitation Inventory; ECG = electrocardiogram; EQ-5D-5L= EuroQol 5-Dimension 5-Level; ESS = Epworth Sleepiness Scale; ET = early termination; 
MMSE = Mini Mental State Examination; NPI = Neuropsychiatric Inventory; PK= Pharmacokinetics; RUD-Lite = Resource Utilization in Dementia-Lite; S-STS = Sheehan 
Suicidality Tracking Scale; TUG= Timed Up and Go
a The Screening period may be extended after discussion with and approval by a Medical Monitor.
b All enrolled patients will have an in-clinic Follow-up visit 30 (+7) days after last dose of study drug for selected safety and efficacy assessments.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
8
c For each patient, a protocol eligibility form will be completed by the site and reviewed by a Medical Monitor for approval prior to participation in the study.
d Only the Agitation/Aggression domain of the NPI will be performed at Screening, and at Visit 3, Visit 4, and Visit 6 (ie, Days 15, 29, and 57).
e Height and weight will be measured at Baseline (Day 1); only weight will be measured at Visit 8 (Day 85/ET).
f At Screening, 3 ECGs will be performed (eg, one after the other).
g ECG will be performed predose and 1 to 1.5 hours postdose at Baseline (Day 1) and Visit 2 (Day 8).
h ECG will be performed at any time at Visit 5 (Day 43) and Visit 8 (Day 85/ET).
i Thyroid function tests (TSH, and reflex T3 and T4 if TSH is abnormal) will be performed at Screening. Glycosylated hemoglobin (HbA1c) test will be performed at Screening 
and Visit 8 (Day 85/ET).
j Urine pregnancy test will be performed for women of child-bearing potential only.
k ESS will be rated only by patients who have a MMSE score of ≥ 10 at Baseline.
l At Visit 2 (Day 8), the PK blood sample will be collected 1 to 4 hours postdose. At Visit 5 (Day 43), the PK blood sample will be collected predose. At Visit 7 (Day 71), the PK 
blood sample will be collected at any time. The time of the last 2 doses of study drug prior to collection of the PK blood sample will be recorded in the clinical database. 
 m At Visit 2 (Day 8), the PK urine sample will be collected 1 to 4 hours postdose.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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OPDC
Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
9
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
TABLE OF CONTENTS
PROTOCOL AGREEMENT...........................................................................................................2
SYNOPSIS3
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES....................................9
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................14
1.
INTRODUCTION......................................................................................................17
1.1.
Rationale for Investigating AVP-786 for Treatment of Agitation in Dementia.........17
1.2.
Rationale for the Study Design...................................................................................18
1.3.
Rationale for AVP-786 Dose......................................................................................18
1.4.
Rationale for the Duration of AVP-786 Dosing.........................................................18
2.
TRIAL OBJECTIVES AND PURPOSE....................................................................19
2.1.
Primary Objective.......................................................................................................19
2.2.
Secondary Objectives .................................................................................................19
3.
INVESTIGATIONAL PLAN.....................................................................................20
3.1.
Overall Study Design..................................................................................................20
3.2.
Study Assessments and Procedures............................................................................21
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................22
4.1.
Patient Inclusion Criteria............................................................................................23
4.2.
Patient Exclusion Criteria...........................................................................................24
4.3.
Patient Withdrawal Criteria........................................................................................25
4.4.
CTSdatabase and Subject Database Authorization.....................................................26
5.
TREATMENT OF PATIENTS..................................................................................27
5.1.
Description of Study Drug..........................................................................................27
5.2.
Concomitant Medications and Nondrug Therapies....................................................27
5.2.1.
Restricted and Prohibited Concomitant Medications .................................................27
5.3.
Treatment Compliance................................................................................................29
5.4.
Randomization and Blinding......................................................................................29
6.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................31
6.1.
Study Drug Composition............................................................................................31
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
10
6.2.
Study Drug Packaging and Labeling..........................................................................31
6.3.
Study Drug Storage.....................................................................................................31
6.4.
Study Drug Administration.........................................................................................31
6.5.
Study Drug Accountability.........................................................................................32
6.5.1.
Receipt of Drug Supplies............................................................................................32
6.5.2.
Record of Dispensing .................................................................................................32
6.6.
Study Drug Handling and Disposal............................................................................32
7.
ASSESSMENT OF EFFICACY ................................................................................33
7.1.
Cohen-Mansfield Agitation Inventory (CMAI)..........................................................33
7.2.
Clinical Global Impression of Severity of Illness-Agitation (CGIS-Agitation).........33
7.3.
Clinical Global Impression of Change-Agitation (CGIC-Agitation) .........................34
7.4.
Neuropsychiatric Inventory (NPI)..............................................................................34
7.5.
EuroQol 5-Dimension 5-Level (EQ-5D-5L) ..............................................................34
7.6.
Resource Utilization in Dementia (RUD) Lite...........................................................35
8.
ASSESSMENT OF SAFETY.....................................................................................36
8.1.
Safety Parameters .......................................................................................................36
8.1.1.
Adverse and Serious Adverse Events.........................................................................36
8.1.1.1.
Definition of Adverse Events .....................................................................................36
8.1.1.2.
Serious Adverse Event................................................................................................37
8.1.1.3.
Reporting Adverse Events..........................................................................................38
8.1.2.
Physical and Neurological Examinations...................................................................38
8.1.3.
Vital Signs ..................................................................................................................39
8.1.4.
Weight and Height......................................................................................................39
8.1.5.
Electrocardiogram (ECG)...........................................................................................39
8.1.6.
Clinical Laboratory Assessments ...............................................................................40
8.1.7.
Pregnancy Tests..........................................................................................................40
8.1.8.
Mini Mental State Examination (MMSE) ..................................................................41
8.1.9.
Epworth Sleepiness Scale (ESS) ................................................................................41
8.1.10.
Sheehan Suicidality Tracking Scale (S-STS) .............................................................41
8.1.11.
Assessment of Risk of Falls for Eligibility.................................................................42
8.1.11.1.
Timed Up and Go (TUG) Test....................................................................................42
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Protocol 20-AVP-786-307
AVP-786
Protocol Amendment 2, Version 3.0
11
8.1.12.
Hachinski Ischemic Scale (Rosen Modification) .......................................................42
9.
SCHEDULE OF EVAUATIONS AND PROCEDURES..........................................43
9.1.
Description of Study Procedures ................................................................................43
9.1.1.
Screening Visit (Days -28 to -1).................................................................................43
9.1.2.
Baseline Visit (Day 1) ................................................................................................44
9.1.3.
Visit 2 (Day 8 ± 3-day window).................................................................................45
9.1.4.
Visit 3 (Day 15 ± 3-day window)...............................................................................47
9.1.5.
Visit 4 (Day 29 ± 3-day window)...............................................................................48
9.1.6.
Visit 5 (Day 43 ± 3-day window)...............................................................................49
9.1.7.
Visit 6 (Day 57 ± 3-day window)...............................................................................50
9.1.8.
Visit 7 (Day 71 ± 3-day window)...............................................................................51
9.1.9.
Visit 8 (Day 85 ± 3-day window) / Early Termination ..............................................52
9.1.10.
Follow-up Visit (30 days post last dose; + 7-day window)........................................53
9.2.
End of Trial.................................................................................................................53
10.
STATISTICS..............................................................................................................54
10.1.
Sample Size Calculations ...........................................................................................54
10.2.
Analysis Populations ..................................................................................................54
10.3.
Handling of Missing Data...........................................................................................54
10.4.
Efficacy Analysis........................................................................................................54
10.4.1.
Primary Efficacy Endpoint Analysis ..........................................................................54
10.4.2.
Key Secondary Analysis.............................................................................................55
10.4.3.
Other Efficacy Endpoint Analysis..............................................................................55
10.4.4.
Control of Experiment-wise Type 1 Error..................................................................56
10.4.5.
Other Efficacy Endpoint Analyses .............................................................................56
10.5.
Interim Analysis..........................................................................................................56
10.6.
Analysis of Demographic and Baseline Characteristics.............................................56
10.7.
Safety Analysis...........................................................................................................56
10.7.1.
Adverse Events...........................................................................................................56
10.7.2.
Clinical Laboratory Data ............................................................................................57
10.7.3.
Physical and Neurological Examination and Vital Sign Data....................................57
10.7.4.
Electrocardiogram Data..............................................................................................57
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10.7.5.
Other Safety Data .......................................................................................................57
10.7.6.
Data and Safety Monitoring Board.............................................................................57
10.8.
Other Analyses............................................................................................................58
10.8.1.
Pharmacokinetic Analysis ..........................................................................................58
10.8.2.
Pharmacodynamic Analysis........................................................................................58
10.8.3.
Pharmacokinetic/Pharmacodynamic Analysis............................................................58
10.8.4.
Pharmacogenomic Analysis........................................................................................58
10.8.5.
Exploratory Endpoint Analysis...................................................................................58
11.
ETHICS ......................................................................................................................59
11.1.
Ethical Conduct of the Study......................................................................................59
11.2.
Institutional Review Board - Ethics Review ..............................................................59
11.3.
Written Informed Consent..........................................................................................59
12.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61
12.1.
Documentation............................................................................................................61
12.2.
Study Monitoring........................................................................................................61
12.3.
Direct Access to Source Data/Documents for Audits and Inspections.......................61
13.
DATA HANDLING AND RECORDKEEPING.......................................................63
13.1.
Data Management and Collection ..............................................................................63
13.2.
Source Data.................................................................................................................64
13.3.
Retention of Records ..................................................................................................64
13.4.
Confidentiality of Study Documents and Patient Records .........................................64
13.5.
Reports........................................................................................................................65
14.
CRITERIA FOR STUDY TERMINATION..............................................................66
15.
PUBLICATION POLICY ..........................................................................................67
16.
LIST OF REFERENCES............................................................................................68
17.
SUMMARY OF CHANGES......................................................................................73
17.1.
Protocol Amendment 2 (Version 3.0) - 15 May 2023................................................73
73
75
76
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LIST OF TABLES
Table 1:
Schedule of Assessments and Visits.............................................................................6
Table 2:
Abbreviations and Specialist Terms...........................................................................14
Table 3:
Restricted and Prohibited Concomitant Medications .................................................28
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol.
Table 2:
Abbreviations and Specialist Terms
Abbreviation
Definition
ADWG
Agitation Definition Working Group
ANCOVA
analysis of covariance 
AVP-786
d6-DM and Q 
BP
blood pressure
CFR
US Code of Federal Regulations
CGIC-Agitation
Clinical Global Impression of Change
CGIS
Clinical Global Impression of Severity
CGIS-Agitation
Clinical Global Impression of Severity of Illness scale for 
Agitation
CMAI
Cohen-Mansfield Agitation Inventory
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CYP
cytochrome P450
d6-DM
deudextromethorphan hydrobromide (or deudextromethorphan)
DEMQOL
Dementia Quality of Life
DMP
data management plan
DSMB
Data and Safety Monitoring Board
DSM-V-TR
Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition, Text Revision
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EP
European Pharmacopoeia
EQ-5D-5L
EuroQol 5-Dimension 5-Level
ESS
Epworth Sleepiness Scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
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Abbreviation
Definition
HbA1c
glycosylated hemoglobin
HR
heart rate
IAP
interim analysis plan
ICF
informed consent form
ICH
International Council for Harmonisation
IEC/EC
Independent Ethics Committee
ITT
intent-to-treat
IRB
Institutional Review Board
IWRS
interactive web-response system
LOCF
last observation carried forward
mADCS-CGIC-Agitation
Modified Alzheimer’s Disease Cooperative Study-Clinical 
Global Impression of Change scale for Agitation
MAOI
monoamine oxidase inhibitor
MedDRA
Medical Dictionary for Regulatory Activities 
mITT
modified intent-to-treat
MMRM
mixed-effect model for repeated measures
MMSE
Mini Mental State Examination
MNAR
missing data being missing not at random
NIA-AA
National Institute on Aging – Alzheimer’s Association
NPI
Neuropsychiatric Inventory
NPI-AA
Neuropsychiatric Inventory Agitation/Aggression
NPI-NH
Neuropsychiatric Inventory – Nursing Home
OC
observed case
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
OTC
over-the-counter
PK
pharmacokinetic
PVC
premature ventricular contractions
Q
quinidine sulfate (or quinidine)
QOL
quality of life
QTcF
QTc by Fridericia’s formula
RUD-Lite
Resource Utilization in Dementia-Lite
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Abbreviation
Definition
SAE
serious adverse event
SAP
statistical analysis plan 
SOC
system organ class 
SNRI
serotonin-norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitors
S-STS
Sheehan Suicidality Tracking Scale
TEAE
treatment-emergent adverse event
TSH
thyroid-stimulating hormone 
TUG
Timed Up and Go
UN
unstructured variance covariance structure
US
United States
USP
United States Pharmacopoeia
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1.
INTRODUCTION
Alzheimer’s disease, the most common form of dementia, is a progressive neurodegenerative 
disease that eventually leads to death. There are an estimated 5.8 million people in the United 
States (US) with Alzheimer’s dementia and this number is expected to reach 14 million by the 
year 2050 1. National estimates of the prevalence of all dementias from population-based studies 
including the Aging, Demographics, and Memory Study (ADAMS), a nationally representative 
sample of older adults, show that 14 percent of people age 71 and older in the US have dementia 
2,3.
Agitation is widely recognized by clinicians as a common and important clinical feature of 
Alzheimer’s disease and other forms of dementia 4,5,6,7,8. Agitation, aggression, depression, 
hallucinations, and delusions are estimated to affect up to approximately 90% of patients with 
Alzheimer’s disease with an increase in prevalence as the disease progresses 4,9. In a meta 
analyses of data from 55 studies, overall prevalence of agitation ranged from 5% to 88% across 
all studies, with 23 studies reporting the prevalence of at least one neuropsychiatric syndrome 
with a range of 40% to 100%. Agitation in patients with dementia is associated with increased 
functional disability, worse quality of life 10,11,12, earlier institutionalization 13, increased 
caregiver burden 14,5,15,16,17,18, increased healthcare costs 19,20,13,21, shorter time to severe dementia 
22,23, and accelerated mortality 23,24. Currently, there is no approved treatment in the US to 
manage agitation in patients with Alzheimer’s disease 25. Pharmacologic treatments for patients 
with agitation in Alzheimer’s disease include off-label use of atypical antipsychotics, selective 
serotonin reuptake inhibitors, benzodiazepines, and anticonvulsants 26,27,28; however, these 
treatments provide only modest efficacy that is offset by relatively poor adherence, safety, and 
tolerability 29,30. It is widely recognized that a safe and effective treatment for patients with 
agitation in Alzheimer’s disease represents a significant unmet need 31. Such a treatment could 
profoundly impact patient care, potentially reduce caregiver burden, and improve overall disease 
prognosis.
1.1.
Rationale for Investigating AVP-786 for Treatment of Agitation in 
Dementia
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 demonstrated 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 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.
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Studies conducted by the Sponsor have shown that d6-deuterium modification of 
dextromethorphan reduces the rate of CYP2D6 metabolism such that a low dose of quinidine is 
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.
Based on the above, further clinical investigation is warranted to explore the potential efficacy 
and safety of AVP-786.
The current study (Study 20-AVP-786-307) is designed to evaluate the efficacy, safety, and 
tolerability of AVP-786 for the treatment of agitation in patients with dementia of the 
Alzheimer’s type.
1.2.
Rationale for the Study Design
The randomized, placebo-controlled, double-blind design reduces sources of bias that are 
inherent in less well-controlled designs. The safety assessments used are standard in clinical 
research and are generally recognized as reliable, accurate, and relevant. The rating scales used 
to assess efficacy are well-established instruments that are widely used in clinical studies of 
agitation in Alzheimer’s disease.
1.3.
Rationale for AVP-786 Dose
Based on the collective efficacy, safety, and tolerability data in the completed Phase 3 studies, 
doses of up to a maximum of 42.63 mg of d6-DM and 4.9 mg of Q administered BID will be 
evaluated in this Phase 3 study. The doses given in the previous AVP-786 studies were within 
this dose range and were generally well tolerated.
1.4.
Rationale for the Duration of AVP-786 Dosing
A drug being developed for treatment of a chronic condition needs to show some evidence of 
persistence of acute effects. A 12-week treatment duration is generally considered by experts and 
regulators as a reasonable time frame to assess efficacy and safety of a compound for chronic 
use.
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2.
TRIAL OBJECTIVES AND PURPOSE
2.1.
Primary Objective
The primary objective is to evaluate the efficacy, safety, and tolerability of AVP-786 compared 
to placebo for the treatment of agitation in patients with dementia of the Alzheimer’s type.
2.2.
Secondary Objectives
The secondary objectives are to:
•
Evaluate the effects of AVP-786 compared to placebo on global assessments of 
severity and improvement of agitation
•
Evaluate the effects of AVP-786 compared to placebo on neuropsychiatric symptoms
•
Evaluate the effects of AVP-786 compared to placebo on measures of quality of life 
and resource utilization
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3.
INVESTIGATIONAL PLAN
3.1.
Overall Study Design
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study with a 
12-week treatment duration. The study consists of a 4-week Screening period, a 12-week 
double-blind treatment period, and a 30-day Follow-up period. Approximately 750 patients with 
agitation of the Alzheimer’s type will be enrolled at approximately 110 centers including the 
United States [US] and Europe.
Screening Period (Day -28 to Day -1)
Patient eligibility will be determined during the Screening visit, which will occur within 4 weeks 
of the Baseline visit. A protocol eligibility form will be completed for each patient and reviewed 
by a Medical Monitor for approval prior to participation in the study.
Double-blind, Treatment Period (12 Weeks)
During the double-blind treatment period, all eligible patients will be randomly assigned to 
receive either AVP-786 or matching placebo. Randomization will be stratified by site and 
baseline concomitant antipsychotic use (yes/no). Study drug will be administered twice daily 
(BID; morning and evening) starting from the Baseline visit (Day 1) through Visit 8 (Day 85).
Follow-up Period
All enrolled patients, whether they complete the study or terminate from the study early for any 
reason, will have a Follow-up visit 30 days after the last dose of study drug for select efficacy 
and safety assessments.
Assessments and Visits:
Patients will attend clinic visits at Screening (Day -28 to -1), Baseline (Day 1), Visit 2 (Day 8), 
Visit 3 (Day 15), Visit 4 (Day 29), Visit 5 (Day 43), Visit 6 (Day 57), Visit 7 (Day 71), Visit 8 
(Day 85; or Early Termination [ET] Visit), and 30 days after the last dose of study drug 
(Follow-up visit).
Study assessments and procedures will be performed at each visit as outlined in the Schedule of 
Assessments and Visits (Table 1). The primary efficacy measure is the Cohen-Mansfield 
Agitation Inventory (CMAI). Secondary efficacy measures include Clinical Global Impression of 
Severity of Illness for Agitation (CGIS-Agitation), Clinical Global Impression of Change for 
Agitation (CGIC-Agitation), Neuropsychiatric Inventory Agitation/Aggression (NPI-AA), NPI 
total, EuroQol 5-Dimension 5-Level (EQ-5D-5L), and Resource Utilization in Dementia-Lite 
(RUD-Lite).
Pharmacokinetic (PK) measurements of plasma concentrations of d6-DM, its metabolites d3-DX 
and d3-3-MM, and Q will be measured from blood samples collected at Visit 2 (Day 8), Visit 5 
(Day 43), and Visit 7 (Day 71). PK measurements of urine concentrations of d6-DM and its 
metabolite d3-DX will be measured from a urine sample collected at Visit 2 (Day 8).
The safety and tolerability of AVP-786 will be assessed by reported AEs, physical and 
neurological examination, vital signs, clinical laboratory measures, resting 12-lead 
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electrocardiograms (ECG), and the following safety scales: Mini-Mental State Examination 
(MMSE), Epworth Sleepiness Scale (ESS), and Sheehan Suicidality Tracking Scale (S-STS).
3.2.
Study Assessments and Procedures
A tabular summary of the schedule of study assessments and procedures by visit is provided in 
the Schedule of Assessments and Visits (Synopsis Table 1). A more detailed description of the 
assessments at each visit is provided in Section 9, Schedule of Evaluations and Procedures.
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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Patients enrolled in this study must have a diagnosis of probable Alzheimer’s disease and must 
present with clinically significant, moderate-to-severe agitation secondary to Alzheimer’s 
disease. 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 32. Neither Alzheimer’s disease 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)33 will be used to select study patients. This proposed definition is limited to 
patients with cognitive impairment and requires: (a) evidence of emotional distress; (b) 1 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 must have clinically significant, moderate-to-severe agitation for at least 
2 weeks prior to Screening that interferes with daily routine per the Investigator’s judgment, and 
who require pharmacotherapy for the treatment of agitation per the Investigator’s judgment after 
an evaluation of reversible factors and a course of nonpharmacological interventions.
An NPI-AA score of ≥ 4 and MMSE score of 8 to 24 (inclusive) at Screening and Baseline are 
required for study participation. Patients must meet an additional predetermined blinded 
eligibility criterion, which will remain blinded to the clinical study site Investigators and staff.
Eligible patients are to have otherwise acceptable and stable general health as required by the 
study protocol and documented by medical history, physical and neurological examination, ECG, 
and clinical laboratory examinations.
Eligible patients must have a caregiver who is able and willing to comply with all required study 
procedures, ensuring that the patient attends all study visits and takes the study drug as 
instructed, including adherence to not administering any prohibited medications during the 
course of the study. Caregivers will also be instructed to record the daily number of capsules 
taken and the time of administration in the patient Diary Card. In addition, caregivers are 
responsible for reporting any changes in patient’s status, including adverse events and standard 
of care setting (eg, becoming a resident in an assisted living facility), as well as providing their 
impression and assessment regarding the investigational treatment to the study team at the 
Investigator’s site. A CMAI caregiver diary will be provided to be used by the caregiver to 
support reporting of behaviors during the CMAI interview process. In order to qualify as a 
reliable informant (ie, caregiver) capable of assessing changes in the patient’s condition during 
this study, the individual must spend a minimum of 2 hours with the patient per day for 4 days 
per week. In addition, this individual should remain as the patient’s caregiver throughout the 
study.
The complete list of inclusion and exclusion criteria for this study are provided in the following 
sections.
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4.1.
Patient Inclusion Criteria
1. Males and females 50 to 90 years of age (inclusive) at the time of informed consent.
2. Diagnosis of probable Alzheimer’s disease according to the 2011 NIA-AA working 
groups criteria. Either outpatients or residents of an assisted living facility, a skilled 
nursing home, a dementia unit, or any other type of facility providing long-term care.
3. MMSE score between 8 and 24 (inclusive) at Screening and Baseline.
4. Patient has clinically significant, moderate-to-severe agitation for at least 2 weeks prior to 
Screening that interferes with daily routine per the Investigator’s judgment.
5. Patients who require pharmacotherapy for the treatment of agitation per the Investigator’s 
judgment, after:
•
An evaluation of reversible factors (eg, pain, infection, or polypharmacy), and
•
A course of nonpharmacological interventions (eg, redirecting behavior, group 
activities, music therapy). 
6. Diagnosis of agitation must meet the International Psychogeriatric Association (IPA) 
provisional definition of agitation.
7. NPI-AA total score (frequency × severity) must be ≥ 4 at Screening and Baseline.
8. Patient must meet an additional predetermined blinded eligibility criterion. 
9. Patient has stable cardiac, pulmonary, hepatic, and renal function per the Investigator’s 
judgment. 
10. No clinically significant findings on the Screening ECGs based on central review and on 
the Baseline predose ECG based on the machine read and Investigator’s evaluation.
11. Women who are of childbearing potential and are sexually active must use an effective 
method of birth control for at least 1 month prior to the Baseline, during participation in 
the study, and for at least 30 days after the last dose of study drug. The following 
requirements must be met: 
•
Women who are 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 (eg, 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.
•
Women who are sterile (ie, 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.
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•
Women who are lactating, pregnant, or plan to become pregnant are not eligible for 
participation in the study. 
12. For restricted and prohibited concomitant medications, patients willing and able to meet 
all protocol requirements for duration of stability or washout prior to study entry and 
during the study (see Table 3 Restricted and Prohibited Concomitant Medications and 
Appendix 1 Prohibited Concomitant Medications).
13. Caregiver must be willing and able to comply with all study procedures, including 
adherence to administering study drug and not administering any prohibited medications 
during the study. The caregiver must spend a minimum of 2 hours with the patient per 
day for at least 4 days per week to qualify as caregiver.
14. 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 agrees to participation (for patients unable to 
provide assent) are allowed.
4.2.
Patient Exclusion Criteria
1. Caregiver is unwilling or unable, in the opinion of the Investigator, to comply with study 
instructions.
2. Patient has dementia predominantly of non-Alzheimer’s type (eg, vascular dementia, 
frontotemporal dementia, Parkinson’s disease, substance-induced dementia).
3. Patients with symptoms of agitation that are not secondary to Alzheimer’s dementia (eg, 
secondary to pain, other psychiatric disorder, or delirium).
4. Patients who have been diagnosed with an Axis 1 disorder (Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition, Text Revision [DSM-5] criteria) including, but 
not limited to: 
•
Schizophrenia, schizoaffective disorder, or other psychotic disorders not related to 
dementia 
•
Bipolar I or II disorder, bipolar disorder not otherwise specified
•
Current Major Depressive Episode: Patients with a history of major depressive 
disorder, that is currently not symptomatic, are eligible. Patients currently on a stable 
dose(s) of allowed antidepressant medication(s) for at least 3 months prior to the 
Screening visit are eligible. 
5. Patients with myasthenia gravis (contraindication for quinidine).
6. Patients with any personal history of complete heart block, QTc prolongation, or 
torsades de pointes.
a.
Screening and Baseline predose 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 (See Section 8.1.5).
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Screening ECGs will be based on central review. Baseline predose ECG will be based 
on the machine read and Investigator’s evaluation; if the QTcF result from the 
machine read is exclusionary, do not administer study drug and please contact a 
Medical Monitor.
b. Presence of premature ventricular contractions (PVCs) as evaluated by a central 
reader and deemed clinically significant by the Investigator.
7. Patients with any family history of congenital QT interval prolongation syndrome.
8. Patients with known hypersensitivity to DM, Q, opiate drugs (codeine, etc), or any other 
ingredient of the study drug.
9. Patients who have ever received DM co-administered with Q or d6-DM co-administered 
with Q.
10. Patients who would be likely to require a prohibited concomitant medication during the 
study (see Table 3, Restricted and Prohibited Concomitant Medications and Appendix 1 
Prohibited Concomitant Medications).
11. Patients with co-existent clinically significant or unstable systemic diseases that could 
confound the interpretation of the safety results of the study (eg, 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 nonmetastatic cancer 
may be allowed. Each case is to be evaluated individually with a Medical Monitor.
12. Patients who are currently participating in or who have participated in other 
interventional (drug or device) clinical study, or found to be a “Virtually Certain” match 
in Clinical Trial Subject Database (CTSdatabase) with a patient who has participated in 
another interventional drug or device study within 30 days of Baseline.
13. Patients with history of postural syncope or any history of unexplained syncope 
(evaluated on a case-by-case basis) within 12 months of Baseline.
14. Patients with a history of substance and/or alcohol abuse within 12 months of Baseline.
15. Patients determined to have a high imminent risk of falls during the study based on a 
clinical evaluation by the Investigator.
16. Patients with evidence of serious risk of suicide at Screening and Baseline based on the 
Sheehan Suicidality Tracking Scale (S-STS), ie, 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.
17. Patients who, in the opinion of the Investigator, Medical Monitor, or sponsor, should not 
participate in the study. 
4.3.
Patient Withdrawal Criteria
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 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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5.
TREATMENT OF PATIENTS
5.1.
Description of Study Drug
Study drug will be provided as opaque hard gelatin capsules with a purple cap and white body. 
Each capsule contains one of the following:
•
AVP-786 capsules
•
Placebo capsules: matching AVP-786 in appearance
Drug supplies will be provided to the site in double-blind, individual, prelabeled blister cards.
5.2.
Concomitant Medications and Nondrug Therapies
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.
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.
For patients who terminate early, the conditions of use for allowed concomitant medications and 
nondrug therapies or prohibited medications do not apply between the ET visit and the 
Follow-up visit. Any use of medications during this period will be at the discretion of the 
Investigator. Patients should allow at least 14 days after stopping study drug before starting a 
monoamine oxidase inhibitor (MAOI).
5.2.1.
Restricted and Prohibited Concomitant Medications
Psychotropic concomitant medications that are either allowed with certain restrictions or 
prohibited are listed in Table 3. A detailed list of prohibited concomitant medications that may 
result in significant drug-drug interactions is provided in Appendix 1.
Due to differences in the commercial availability of allowed concomitant medications in the 
specific country, please contact a Medical Monitor to discuss any alternative medications not 
listed below.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Table 3:
Restricted and Prohibited Concomitant Medications
Medication
Prior to Study Entry
During Double-Blind 
Treatment Period
1.
Medications to treat 
Alzheimer’s disease (eg, 
cholinesterase inhibitors, 
memantine, or other 
cognitive enhancers approved 
in the respective country)
Allowed provided that the dose has 
been stable for at least 3 months prior 
to the Screening visit, AND there is no 
change in dose or discontinuation 
within the same time period 
Should remain on the same dose 
throughout the duration of the 
study, except when medically 
indicated due to a change in the 
underlying medical condition
Atypical Antipsychotics
• except clozapine 
• except brexpiprazole
Allowed provided that the dose has 
been stable for at least 1 month prior to 
the Screening visit, AND there is no 
change in dose or discontinuation 
within the same time period
Should remain on the same dose 
throughout the duration of the 
study
Clozapine
Not allowed within 1 month prior to the 
Screening visit
Prohibited
Typical Antipsychotics 
Not allowed within 1 month prior to the 
Screening visit
Prohibited
2.
Brexpiprazole
Not allowed within 1 month prior to the 
Screening visit
Prohibited
Antidepressants 
• select antidepressants listed 
below are restricted or 
prohibited
Allowed provided that the dose has 
been stable for at least 3 months prior 
to the Screening visit and is within the 
range specified in the prescribing 
information for that medication, AND 
there is no change in dose or 
discontinuation within the same time 
period
Should remain on the same dose 
throughout the duration of the 
study
Paroxetine
Allowed with a maximum dose of 
10 mg/day
Should remain on the same dose 
throughout the duration of the 
study
Trazodone
Allowed with a maximum dose of 
50 mg/day
Should remain on the same dose 
throughout the duration of the 
study
Nefazodone
Not allowed within 3 months prior to 
the Screening visit
Prohibited
Tricyclic Antidepressants 
Not allowed within 3 months prior to 
the Screening visit
Prohibited
3.
Monoamine Oxidase 
Inhibitors (MAOI)
Not allowed within 3 months prior to 
the Screening visit
Prohibited
Patients should allow at least 
14 days after stopping study 
drug before starting an MAOI
4.
Benzodiazepines
Not allowed within 1 month prior to the 
Screening visit
Prohibited
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Medication
Prior to Study Entry
During Double-Blind 
Treatment Period
5.
Hypnotic Sleep Agents 
(eg, zolpidem, zaleplon, 
zopiclone, eszopiclone, or 
other sleep agent approved in 
the respective country)
Allowed if the dose of the sleep agent 
for insomnia was taken on a regular 
basis for at least 1 month prior to the 
Screening visit, AND there is no 
change in dose or frequency, or 
discontinuation in the same time period
Should remain on the same dose 
and at the same frequency 
throughout the duration of the 
study
Other allowed psychotropic 
medications that may impact 
agitation (eg, mood 
stabilizers, antiepileptics)
•
select medications listed 
below are prohibited
Allowed provided that the dose has 
been stable for at least 1 month prior to 
the Screening visit, AND there is no 
change in dose or discontinuation 
within the same time period
Should remain on the same dose 
throughout the duration of the 
study
6. 
Atomoxetine, carbamazepine, 
fosphenytoin, pentobarbital, 
phenobarbital, phenytoin, 
primidone
Not allowed within 1 month prior to the 
Screening visit
Prohibited
7.
Other prohibited concomitant 
medications (see Appendix 1)
Not allowed within 2 weeks or 
5 half-lives (whichever is longer) prior 
to the Baseline visit
Prohibited
5.3.
Treatment Compliance
Patients and caregivers will be instructed to return all dispensed study drug, including unused 
and used empty blister cards, to the clinic on Visits 2 through 8 (Days 8, 15, 29, 43, 57, 71, and 
85/ET). For this study, compliance will be defined as when a patient takes at least 80% of their 
scheduled doses (compliance range 80% to 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 on Visits 2 through 8, 
or at the time of early study discontinuation. Patients should bring their Diary Card to each of 
these visits for compliance review; the Diary Card will be returned to the patient and collected at 
the next visit, if applicable. 
5.4.
Randomization and Blinding
Eligible patients will be randomized to either treatment with AVP-786 or placebo according to a 
randomization scheme devised by the Sponsor or its representative and managed within an 
interactive web response system (IWRS). The randomization will be stratified by site and 
baseline concomitant antipsychotic use (yes/no).
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 unblinding, ideally the Investigator should contact the study Medical Monitor 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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to discuss the unmasking of a patient. If this is not possible, the study Medical Monitor should be 
notified as soon as possible.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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6.
STUDY DRUG MATERIALS AND MANAGEMENT
6.1.
Study Drug Composition
Each capsule of study drug will contain one of the following:
•
AVP-786
•
Matching Placebo: identical in appearance to AVP-786 capsules; containing inactive 
ingredients only
The inactive ingredients are croscarmellose sodium, microcrystalline cellulose, colloidal silicone 
dioxide, and magnesium stearate.
Study drug will be prepared, packaged, and labeled in accordance with Good Manufacturing 
Practice (GMP) guidelines, International Council on Harmonisation (ICH), Good Clinical 
Practice (GCP) guidelines, and applicable laws and regulations.
6.2.
Study Drug Packaging and Labeling
The investigators will be supplied with prelabeled, individually prepackaged blister cards 
(1-week and 2-week blister cards). The panel of the 1-week blister card (1 week of study drug) 
consists of 3 rows of 7 capsules; one row for the morning dose, one row for the evening dose, 
and one row for extra supplies. The panel of the 2-week blister card (2 weeks of study drug) 
consists of 5 rows of 7 capsules; one row for the morning and one row for the evening dose for 
the first week and second week, and one row for extra supplies.
All labels will contain the protocol number, product name, blister card kit number (Med ID No.), 
an investigational drug warning, dosage instructions to take one capsule in the morning (AM) 
and one capsule in the evening (PM), storage conditions, and company name. The blister card 
label will consist of either a 2-panel label or booklet label. Both will have a detachable panel that 
will be removed and affixed to the study drug Dispensing Log page at the time of dispensing.
6.3.
Study Drug Storage
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). 
6.4.
Study Drug Administration
All patients will receive study drug according to the blister card kit numbers assigned by an 
IWRS randomization scheme. Designated staff at each site will dispense study drug. Study drug 
should be administered to the patient by the caregiver, family member, nursing home staff, or 
self-administered with supervision, except on applicable clinic visit days when patients will be 
administered their dose of study drug at the clinic in the presence of site personnel, regardless of 
the time of day; the morning dose of study drug will be administered in the clinic at 
Baseline (Day 1), Visit 2 (Day 8), and Visit 5 (Day 43). For the remaining visits (Visit 3 
[Day 15], Visit 4 [Day 29], Visit 6 [Day 57], Visit 7 [Day 71], and Visit 8 [Day 85]/ET), the 
Abbreviated Clinical Study Report 20-AVP-786-307
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morning dose of study drug can be administered at home prior to the clinic visit; the time of the 
morning dosing should be noted by the patient/caregiver.
Patients and caregivers will be instructed that the patient should take the study drug 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. Patient’s missed doses will be 
noted in the electronic case report form (eCRF).
All study drug will be supplied and administered in a double-blind manner throughout the entire 
duration of the study. 
6.5.
Study Drug Accountability
6.5.1.
Receipt of Drug Supplies
The investigator is responsible for maintaining an inventory of each shipment of study drug 
received and comparing it with the accompanying Drug Accountability Report/Material Shipping 
Form, as well as completing the receipt verification in IWRS. 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 study drug supplied is for use only in this study and should not be used for 
any other purpose. All blister card kit numbers will also be recorded and tracked at the site using 
the Drug Accountability Log.
6.5.2.
Record of Dispensing
Accurate recording of all study drug 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 study drug was dispensed; (ii) the date(s) and quantity of the study 
drug dispensed to the patient; and (iii) the blister card kit number assigned to the patient via 
IWRS.
Additionally, the detachable panel of the label on each blister card will be removed and affixed 
to the study drug Dispensing Log page at the time of dispensing. The detachable panel contains 
the study number and kit number (Med ID No.). Space is provided on the affixed part of the label 
to record patient number, the visit week and dispense date.
6.6.
Study Drug Handling and Disposal
At the end of the study, all unused investigational supplies must be inventoried on the Drug 
Accountability Log and returned to the sponsor or its representative, along with a completed and 
signed Drug Accountability Report/Material Shipping Form. Any study drug returns will be 
reported in IWRS. If any study drug is lost or damaged, it should be indicated on the form and 
should be reported in IWRS.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Protocol Amendment 2, Version 3.0
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7.
ASSESSMENT OF EFFICACY
Whenever possible, each patient and caregiver should have the rating scales administered by the 
same raters throughout the study, for consistency of ratings. The following scales MUST be 
administered by the same rater at each visit: CMAI, CGIS-Agitation, CGIC-Agitation, and NPI.
7.1.
Cohen-Mansfield Agitation Inventory (CMAI)
The CMAI will be used as the primary efficacy measure in this study. The CMAI (long-form 
version) 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 34. These distinct agitation syndromes 
include: aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior 
35. Scores for the 3 dimensions will be derived based on the factor structure described by 
Rabinowitz, et al, 2005 36; further details are provided in the statistical analysis plan (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 the CMAI.
The CMAI will be assessed at Screening (Day -28 to Day -1), Baseline (Day 1), Visit 2 (Day 8), 
Visit 3 (Day 15), Visit 4 (Day 29), Visit 5 (Day 43), Visit 6 (Day 57), Visit 7 (Day 71), Visit 8 
(Day 85/ET), and the Follow-up visit (30 days postdose). The CMAI must be administered by 
the same rater at each visit.
7.2.
Clinical Global Impression of Severity of Illness-Agitation 
(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 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 trials 37,38,39,40,41 and is easy 
and quick to administer, provided that the clinician knows the patient well 42.
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 43,44,45.
The CGIS-Agitation 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-Agitation will 
be assessed at Screening (Day -28 to Day -1), Baseline (Day 1), Visit 2 (Day 8), 
Visit 3 (Day 15), Visit 4 (Day 29), Visit 5 (Day 43), Visit 6 (Day 57), Visit 7 (Day 71), Visit 8 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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(Day 85/ET), and the Follow-up visit (30 days postdose). The CGIS-Agitation must be 
administered by the same rater at each visit.
7.3.
Clinical Global Impression of Change-Agitation (CGIC-Agitation)
The CGIC-Agitation is a 7-point (1-7) scale (1 = very much improved; 7 = very much worse) 
that assesses the change in the severity of agitation in this study 42. The CGIC-Agitation 
evaluation will be conducted at Visit 2 (Day 8), Visit 3 (Day 15), Visit 4 (Day 29), Visit 5 
(Day 43), Visit 6 (Day 57), Visit 7 (Day 71), and Visit 8 (Day 85/ET). The CGIC-Agitation must 
be administered by the same rater at each visit.
7.4.
Neuropsychiatric Inventory (NPI)
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 46. 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).
The NPI will be administered to the patient’s caregiver at Baseline (Day 1), Visit 2 (Day 8), 
Visit 5 (Day 43), Visit 7 (Day 71), and Visit 8 (Day 85/ET). Only the Agitation/Aggression 
domain of the NPI (NPI-AA) will be administered to the patient’s caregiver at Screening 
(Day -28 to Day -1), Visit 3 (Day 15), Visit 4 (Day 29), and Visit 6 (Day 57). The recall period 
will be 2 weeks for all the visits. The NPI must be administered by the same rater at each visit. 
The NPI nursing-home version (NPI-NH) will be used for patients from in-patient or assisted 
living facilities.
7.5.
EuroQol 5-Dimension 5-Level (EQ-5D-5L)
The EQ-5D-5L is a generic questionnaire measuring health-related quality of life and consists of 
a descriptive system and the EuroQol Visual Analogue Scale (EQ VAS) 47. The descriptive 
system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) and each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. The EQ VAS records the respondent’s self-
rated health on a vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable 
health state’ and ‘Worst imaginable health state’. This information can be used as a quantitative 
measure of health outcome as judged by the individual respondents. There are 2 versions of the 
EQ-5D-5L, a version rated by the patient and a version (EQ-5D-5L-proxy) rated by caregiver. 
The patient version will be rated only by patients with an MMSE score of ≥ 10 at the Baseline 
visit.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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The EQ-5D-5L-proxy (and EQ-5D-5L for patients with MMSE ≥ 10) will be assessed at 
Baseline (Day 1) and Visit 8 (Day 85/ET).
7.6.
Resource Utilization in Dementia (RUD) Lite
The RUD is used to calculate healthcare costs associated with dementia 48. It evaluates dementia 
patients’ utilization of formal and informal healthcare resources, including hospitalizations and 
doctor visits, living assistance, and time spent by nonprofessional caregivers. Within the context 
of clinical trials, the RUD is often used to determine the cost effectiveness of new 
pharmaceutical treatments 49.
The RUD is administered as a semi-structured interview with the patient’s primary caregiver, 
and contains 2 sections; one focusing on caregiver impact (loss of work and leisure time incurred 
by caregiver) and the other focusing on the patient’s use of healthcare resources. The total 
healthcare costs associated with the patient’s dementia can be estimated by multiplying the 
number of units used (eg, hours of caregiver time, visits to doctors, nights in accommodation) by 
the corresponding unit price vector.
The RUD-Lite (RUD 5.0) is a shorter version of the RUD developed to reduce the interview 
burden on caregivers. Questions related to caregiver resource use (eg, work status, respite or 
hospital care, social services, day care, or drug use), which in general is low for caregivers, have 
been removed from the RUD-Lite 50. 
The RUD-Lite will be assessed at Baseline (Day 1) and Visit 8 (Day 85/ET).
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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8.
ASSESSMENT OF SAFETY
8.1.
Safety Parameters
8.1.1.
Adverse and Serious Adverse Events
8.1.1.1.
Definition of Adverse Events
An adverse event (AE) is any untoward medical occurrence or unintended change (eg, physical, 
psychological, or behavioral), including inter-current illness, whether considered related to study 
drug 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 study drug, whether or not considered related to the study drug. 
Changes associated with normal growth and development that do not vary in frequency or 
magnitude from that ordinarily anticipated clinically are not AEs (eg, onset of menstruation 
occurring at a physiologically appropriate time).
Clinical AEs should be described by diagnosis and not by symptoms when possible (eg, 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 severity 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 drug 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 study 
drug administration; and/or follows a known response pattern to the study 
drug; but could have been produced by other factors such as the patient’s 
clinical state, therapeutic interventions, or concomitant medications 
administered to the patient
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Related: 
the event follows a reasonable temporal sequence from the time of study 
drug administration; and follows a known response pattern to the study 
drug; and cannot be reasonably explained by other factors such as the 
patient’s clinical state, therapeutic interventions, or concomitant 
medications administered to the patient
8.1.1.2.
Serious Adverse Event
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, ie, 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 necessarily considered 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 reported 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 
(ie, 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 drug 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 child-bearing 
potential of a male patient in the study becomes pregnant within 30 days after his last dose of 
study drug or study completion, whichever is greater.
The term ‘severe’ is a measure of intensity; thus, a severe AE is not necessarily serious. For 
example, nausea of several hours duration may be rated as severe but may not be clinically 
serious.
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16.1.1 Protocol and Protocol Amendments
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8.1.1.3.
Reporting Adverse Events
Caregivers will be queried regarding AEs at each clinic visit after the Screening visit (Baseline 
[Day 1], Visits 2-8 [Days 8, 15, 29, 43, 57, 71, and 85/ET], and Follow-up visit). Only treatment 
emergent adverse events (TEAE) that occur after administration of the first dose of study drug 
will be captured for the purposes of the study. Any intercurrent AEs that occur after the signing 
of the informed consent and prior to the patient’s first dose of study drug will be captured as 
medical history. In the instance that the site becomes aware of any such intercurrent adverse 
events subsequent to confirmation and approval of eligibility for an enrolled patient, the site 
should update the medical history records to reflect this updated information and ensure that the 
updated information is provided to the Medical Monitor. Any AE newly reported after receiving 
the last dose of study drug and up until 30 days after receiving the last dose of study drug will be 
followed.
The Sponsor may request additional information on certain events, such as falls. Event to 
Monitor data collection forms and completion guidelines will be provided for the Investigator to 
complete for such events. These forms should be submitted to the Sponsor as specified on the 
form.
A death occurring during the study, or which comes to the attention of the Investigator within 
30 days after stopping the study drug whether considered drug-related or not, must be reported to 
the sponsor.
For all SAEs the investigator should consult with the Sponsor’s Medical Monitor or designated 
representative as needed and report any SAE via the Serious Adverse Event Reporting (SAER) 
Form by fax/email (as detailed below) no later than 24 hours after becoming aware of the event. 
The SAE must be assessed for the following details: seriousness criteria of the event, SAE start 
date, SAE stop date, severity, relationship to study drug, action taken regarding study drug, and 
outcome to date. The narrative section of the form may be used to detail any treatment 
information.
SAE and Events to Monitor reporting by FAX or e-mail correspondence:
E-mail:
Preliminary (initial) reports will be followed by detailed descriptions, which may include copies 
of hospital records/discharge summaries, autopsy reports, death certificates, and other related 
documents as requested.
The Institutional Review Board/Independent Ethics Committee (IRB/IEC/EC) will be notified of 
such an event in writing as soon as is practical in compliance with federal and local regulations. 
8.1.2.
Physical and Neurological Examinations
Physical and neurological examinations will be performed at Screening (Day -28 to Day -1) and 
Visit 8 (Day 85/ET). 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 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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system. The physical and neurological examinations should be performed by the same person 
each time, whenever possible.
Physical and neurological examination abnormalities determined by the investigator to be 
clinically significant at Screening should be recorded as medical history.
Any clinically significant changes in physical and neurological examination findings from the 
screening examination should be recorded as AEs.
8.1.3.
Vital Signs
Orthostatic blood pressure (BP) and heart rate (HR) measurements will be performed at all clinic 
visits, except the Follow-up visit. 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.
8.1.4.
Weight and Height
Height and weight will be measured at Baseline (Day 1); only weight will be measured at Visit 8 
(Day 85/ET).
8.1.5.
Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at Screening, Baseline, Visit 2 (Day 8), Visit 5 
(Day 43), and Visit 8 (Day 85/ET). At Screening, 3 ECGs will be performed (eg, one after the 
other). At Baseline (Day 1) and Visit 2 (Day 8), 2 ECGs will be performed; one predose and one 
postdose 1 to 1.5 hours after study drug dosing. An ECG will be performed at any time at Visit 5 
(Day 43) and Visit 8 (Day 85/ET).
ECG equipment will be provided by the central reader. ECG data will be recorded at the study 
center and will include general findings, heart rate (beats/minute), QRS complex, PR and QTc 
intervals (milliseconds). Results will be provided by the central reader to the investigators within 
24 hours. ECG abnormalities present at Screening will be recorded as medical history. Any 
changes from the ECG status at Screening visit that are deemed to be clinically significant by the 
investigator should be captured as AEs. Any clinically significant abnormal ECG should be 
discussed with a Medical Monitor and, if necessary, be repeated within a 1-week period.
For eligibility to enroll in the study, the QTcF assessment of the 3 ECGs conducted at Screening 
will be based on the central review. A patient will be excluded if 2 of the 3 Screening ECGs have 
a QTcF > 450 msec in males and > 470 msec in females, unless due to ventricular pacing. If only 
1 Screening ECG has a QTcF > 450 msec in males and > 470 msec in females, which is not 
reproduced in either of the other 2 Screening ECGs, then the patient may be eligible for the 
study. The assessment of ECGs conducted at Baseline will be based on the machine read and 
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investigator evaluation of the read. If the Baseline predose ECG QTcF result from the machine 
read is exclusionary, the patient should not be dosed and a Medical Monitor should be consulted.
8.1.6.
Clinical Laboratory Assessments
Unless otherwise specified, the following clinical laboratory assessments are to be performed at 
Screening (Day -28 to Day -1), Visit 5 (Day 43), and Visit 8 (Day 85/ET):
•
Blood chemistry (calcium, magnesium, phosphorus, glucose, sodium, potassium, 
chloride, carbon dioxide, blood urea nitrogen, serum creatinine, uric acid, albumin, 
total bilirubin, alkaline phosphatase, lactate dehydrogenase, aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase, alanine 
aminotransferase/serum glutamic pyruvic transaminase, creatine kinase, 
gamma-glutamyl transferase, triglycerides, total protein, and total cholesterol)
•
Hematology (red blood cell count, hemoglobin, hematocrit, white blood cell [WBC] 
count, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, platelet 
count, and morphology) 
•
Urinalysis (pH, specific gravity, protein, glucose, ketones, blood, leucocyte esterase, 
nitrates, and microscopic appearance)
•
Thyroid function tests (TSH, and reflex T3 and T4 if TSH is abnormal) at Screening 
visit only
•
Glycosylated hemoglobin (HbA1c) test at the Screening visit and Visit 8 (Day 85) 
only
•
CYP2D6 genotyping at Visit 2 (Day 8) only
•
Amyloid β biomarker at Visit 2 (Day 8) only
Any patients with clinically significant abnormal laboratory test results may be required by a 
Medical Monitor 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. 
8.1.7.
Pregnancy Tests
Urine pregnancy tests are to be performed for women of childbearing potential at Screening (Day 
-28 to Day -1), Baseline (Day 1), and Visit 8 (Day 85/ET).
All female patients of childbearing potential should be instructed to use appropriate birth control 
methods for up to 4 weeks following the last dose of study drug.
Women of childbearing potential who are sexually active must use an effective method of birth 
control for at least 1 month prior to randomization, during the course of the study, and for at least 
30 days after the last dose of study drug. The following requirements must be met:
•
Women 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 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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spermicide. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence for the duration of exposure to 
study drug, or withdrawal are not acceptable methods of contraception.
•
Women who are sterile (ie, 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.
•
Women who are lactating, pregnant, or plan to become pregnant are not eligible for 
participation in the study. 
8.1.8.
Mini Mental State Examination (MMSE)
The MMSE is a brief 30-point questionnaire test that is used to screen for cognitive impairment. 
It is commonly used in medicine to screen for dementia. It is also used to estimate the severity of 
cognitive impairment at a specific time and to follow the course of cognitive changes in an 
individual over time, thus making it an effective way to document an individual’s response to 
treatment. The MMSE scale comprises 11 questions or simple tasks concerning orientation, 
memory, attention, and language to evaluate the patient’s cognitive state 51. The MMSE total 
score ranges from 0 to 30, with higher scores indicating better cognitive function. It requires only 
5 to 10 minutes for a trained rater to administer it.
The MMSE will be assessed at Screening (Day -28 to Day -1), Baseline (Day 1), and Visit 8 
(Day 85).
8.1.9.
Epworth Sleepiness Scale (ESS)
The ESS is an 8-item questionnaire that is used to measure sleepiness by rating the probability of 
falling asleep on 8 different situations that most people engage in during the day 52. The 
questions are rated on a 4-point scale (0 to 3) where 0 = would never doze, 1 = slight chance of 
dozing, 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) and Visit 8 (Day 85/ET) for patients with an 
MMSE score of ≥ 10 at the Baseline visit.
8.1.10.
Sheehan Suicidality Tracking Scale (S-STS)
The S-STS is a prospective scale that assesses treatment-emergent suicidal thoughts and 
behaviors 53. Each item of the S-STS is scored on a 5-point Likert scale (0 = not at all; 1 = a 
little; 2 = moderate; 3 = very; and 4 = extremely). The S-STS can be analyzed as individual item 
scores, suicidal ideation subscale score, suicidal behavior subscale score, or total score. For the 
Screening visit, the timeframe for the items on the scale will be ‘in the past 6 months’ and for all 
other visits it will be ‘since last visit’.
The S-STS will be assessed at Screening (Day -28 to Day -1), Baseline (Day 1), and Visit 8 
(Day 85/ET). Any change in the S-STS score indicating the presence of suicidality should be 
evaluated by the investigator and reported to a Medical Monitor.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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8.1.11.
Assessment of Risk of Falls for Eligibility
8.1.11.1.
Timed Up and Go (TUG) Test
The TUG test measures the time (in seconds) taken for an individual to stand up from a standard 
armchair, walk 3 meters, turn, walk back to the chair and sit down. It is a commonly used scale 
for measuring functional mobility and risk of falls 54,55. The TUG test will be performed only at 
Screening (Day -28 to Day -1) to assess the risk of falls for the purpose of eligibility for the 
study.
8.1.12.
Hachinski Ischemic Scale (Rosen Modification)
The Rosen-modified Hachinski Ischemic Scale assesses whether a patient’s dementia is likely 
due to vascular causes by the response to 8 questions:  abrupt onset, stepwise deterioration, 
somatic complaints, emotional incontinence, history of hypertension, history of stroke, focal 
neurologic signs, and focal neurologic symptoms 56. The total score ranges from 0 to 12, with 
higher scores indicating a greater risk of vascular dementia. The Rosen-modified Hachinski 
Ischemic Scale will be completed at the Screening visit to assess the risk of vascular dementia 
and eligibility for the study by the same physician who performs the neurological examination.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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9.
SCHEDULE OF EVAUATIONS AND PROCEDURES
A schedule of evaluations and procedures by visit is provided in Table 1.
9.1.
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 predefined study assessment results. Further instructions will be 
provided in the IWRS Site Manual.
9.1.1.
Screening Visit (Days -28 to -1)
The following procedures will be performed at Screening (within 28 days prior to Day 1). The 
screening period may be extended after discussion with and approval by a 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. Review inclusion/exclusion criteria (protocol eligibility form completed by site).
3. Medical, psychiatric, and neurological history will be reviewed and recorded, including 
patient demographics, any prior and concomitant medications (including over-the-counter 
[OTC], vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
4. Risk assessment for falls will be performed (worksheet and TUG test).
5. Vital signs will be measured and recorded.
6. Physical and neurological examination will be performed.
7. Three resting 12-lead ECGs will be performed.
8. A blood and urine specimen will be collected for safety laboratory assessments (including 
thyroid function tests and Hb A1c).
9. A urine pregnancy test will be performed for women of childbearing potential only 
(Section 8.1.7).
10. The following assessments will be completed (the CMAI and NPI-AA should be 
administered before the CGIS-Agitation):
•
CMAI
•
NPI-AA domain; a score of ≥ 4 is required for study entry
•
CGIS-Agitation
•
MMSE; a score between 8 and 24 (inclusive) is required for study entry
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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•
S-STS
11. Register the Screening visit in IWRS.
Following screening procedures for assessment of inclusion and exclusion criteria, the site will 
complete a protocol eligibility form to be reviewed by a Medical Monitor for approval prior to 
participation in the study. Patients deemed eligible by the Investigator and a Medical Monitor 
will proceed to the Baseline visit of the study. 
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. 
9.1.2.
Baseline Visit (Day 1)
The Baseline visit (Day 1) should occur in the morning. The following procedures will be 
performed.
Before Dosing: 
1. Review inclusion/exclusion criteria.
2. Vital signs will be measured and recorded.
3. Weight and height will be measured and recorded.
4. A resting 12-lead ECG will be performed (predose).
5. A urine pregnancy test will be performed for patients of childbearing potential only 
(Section 8.1.7).
6. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
7. The following assessments will be completed (the CMAI and NPI should be administered 
before the CGIS-Agitation):
•
CMAI
•
NPI
•
CGIS-Agitation
•
EQ-5D-5L
•
RUD-Lite
•
MMSE
•
ESS (only for patients with an MMSE score of ≥ 10 at Baseline)
•
S-STS
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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Patients will proceed with the Baseline visit once it is determined that they satisfy all of the 
inclusion and none of the exclusion criteria (on the basis of the Screening and Baseline 
assessments described above) and will be assigned with a blister card kit number via IWRS.
Study Drug Dosing:
The first dose of study drug will be administered at the clinic regardless of the time of day from 
the AM strip of the blister card (1-week blister card) after predose assessments are completed; 
note the time of dosing. 
After Dosing:
1. A resting 12-lead ECG will be performed (1 to 1.5 hours postdose). 
2. The caregiver will be queried regarding AEs.
3. Patient Diary Card and a blister card (1-week blister card) will be dispensed.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study drug twice-daily (1 capsule of 
study drug from the top row [AM] of blister card in the morning and 1 capsule of study drug 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 
4 hours) for 7 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 drug and patient’s Diary Card at each study visit. For the next scheduled visit 
(Visit 2, Day 8), caregivers will be advised that the patient’s morning dose of study drug will be 
administered at the clinic. 
A CMAI caregiver diary will be provided to be used by the caregiver to support reporting of 
behaviors during the CMAI interview process.
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
9.1.3.
Visit 2 (Day 8 ± 3-day window)
Visit 2 (Day 8) should occur in the morning prior to the morning dose of study drug. The 
following procedures will be performed.
Before Dosing:
1. Vital signs will be measured and recorded.
2. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
3. A resting 12-lead ECG will be performed (predose).
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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4. The following assessments will be completed (the CMAI and NPI should be administered 
before the CGIS-Agitation and CGIC-Agitation):
•
CMAI
•
NPI
•
CGIS-Agitation
•
CGIC-Agitation
5. Register the study visit in IWRS and a blister card kit number will be assigned to patient 
(1-week blister card).
Study Drug Dosing:
The morning dose of study drug will be administered at the clinic from the AM strip of the new 
blister card (1-week blister card) after predose assessments are completed; note the time of 
dosing.
After Dosing:
1. A resting 12-lead ECG will be performed (1 to 1.5 hours postdose).
2. A blood and urine sample will be collected for PK assessments (1 to 4 hours postdose).
3. A blood sample will be collected for CYP2D6 genotyping.
4. A blood sample will be collected for amyloid β biomarker.
5. Unused study drug will be accounted for compliance, and a new blister card will be 
dispensed (1-week blister card).
6. Patient’s Diary Card will be reviewed for compliance and returned to the patient. 
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study drug twice-daily (1 capsule of 
study drug from the top row [AM] of blister card in the morning and 1 capsule of study drug 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 
4 hours) for 7 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 drug and the patient’s Diary Card at each study visit. For the next scheduled 
visit (Visit 3, Day 15), caregivers will be advised to administer the morning dose of study drug to 
the patient prior to the clinic appointment and note the time of dosing.
A CMAI caregiver diary will be provided to be used by the caregiver to support reporting of 
behaviors during the CMAI interview process.
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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9.1.4.
Visit 3 (Day 15 ± 3-day window)
Visit 3 (Day 15) should occur in the morning. The morning dose of study drug can be 
administered at home any time prior to the visit; the time of dosing should be noted by the 
patient/caregiver.
The following procedures will be performed at Visit 3:
1. Vital signs will be measured and recorded.
2. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
3. The following assessments will be completed (the CMAI and NPI-AA should be 
administered before the CGIS-Agitation and CGIC-Agitation):
•
CMAI
•
NPI-AA
•
CGIS-Agitation
•
CGIC-Agitation
4. Register study visit in IWRS and a blister card kit number will be assigned to patient 
(2-week blister card).
5. Unused study drug will be accounted for compliance, and a new blister card will be 
dispensed (2-week blister card). 
6. Patient’s Diary Card will be reviewed for compliance and returned to the patient. 
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study drug twice-daily (1 capsule of 
study drug from the top row [AM] of blister card in the morning and 1 capsule of study drug 
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 drug and the patient’s Diary Card at each study visit. For the next scheduled 
visit (Visit 4, Day 29), caregivers will be advised to administer the morning dose of study drug to 
the patient prior to the clinic appointment and note the time of dosing.
A CMAI caregiver diary will be provided to be used by the caregiver to support reporting of 
behaviors during the CMAI interview process.
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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9.1.5.
Visit 4 (Day 29 ± 3-day window)
Visit 4 (Day 29) should occur in the morning. The morning dose of study drug can be 
administered at home any time prior to the clinic visit; the time of dosing should be noted by the 
patient/caregiver.
The following procedures will be performed at Visit 4:
1. Vital signs will be measured and recorded.
2. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
3. The following assessments will be completed (the CMAI and NPI-AA should be 
administered before the CGIS-Agitation and CGIC-Agitation):
•
CMAI
•
NPI-AA
•
CGIS-Agitation
•
CGIC-Agitation
4. Register study visit in IWRS and a blister card kit number will be assigned to patient 
(2-week blister card).
5. Unused study drug will be accounted for compliance, and a new blister card will be 
dispensed (2-week blister card). 
6. Patient’s Diary Card will be reviewed for compliance and returned to the patient. 
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study drug twice-daily (1 capsule of 
study drug from the top row [AM] of blister card in the morning and 1 capsule of study drug 
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 drug and the patient’s Diary Card at each study visit. For the next scheduled 
visit (Visit 5, Day 43), caregivers will be advised that the patient’s morning dose of study drug 
will be administered at the clinic.
A CMAI caregiver diary will be provided to be used by the caregiver to support reporting of 
behaviors during the CMAI interview process.
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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9.1.6.
Visit 5 (Day 43 ± 3-day window)
Visit 5 (Day 43) should occur in the morning prior to the morning dose of study drug. The 
following procedures will be performed at Visit 5.
Before Dosing:
1. A blood sample will be collected for safety laboratory assessments and PK assessments.
The following procedures may be performed at any time: 
1. Vital signs will be measured and recorded.
2. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
3. A resting 12-lead ECG will be performed (at any time during this visit).
4. The following assessments will be completed (the CMAI and NPI should be administered 
before the CGIS-Agitation and CGIC-Agitation):
•
CMAI
•
NPI
•
CGIS-Agitation
•
CGIC-Agitation
5. Register study visit in IWRS and a blister card kit number will be assigned to patient 
(2-week blister card).
6. Unused study drug will be accounted for compliance, and a new blister card will be 
dispensed (2-week blister card). 
7. Patient’s Diary Card will be reviewed for compliance and returned to the patient. 
Study Drug Dosing:
The morning dose of study drug will be administered at the clinic from the AM strip of the new 
blister card (2-week blister card) after predose assessments are completed; note the time of 
dosing.
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study drug twice-daily (1 capsule of 
study drug from the top row [AM] of blister card in the morning and 1 capsule of study drug 
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 drug and the patient’s Diary Card at each study visit. For the next scheduled 
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16.1.1 Protocol and Protocol Amendments
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visit (Visit 6, Day 57), caregivers will be advised to administer the morning dose of study drug to 
the patient prior to the clinic appointment and note the time of dosing.
A CMAI caregiver diary will be provided to be used by the caregiver to support reporting of 
behaviors during the CMAI interview process.
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
9.1.7.
Visit 6 (Day 57 ± 3-day window)
Visit 6 (Day 57) should occur in the morning. The morning dose of study drug can be 
administered at home any time prior to the clinic visit; the time of dosing should be noted by the 
patient/caregiver.
The following procedures will be performed at Visit 6:
1. Vital signs will be measured and recorded.
2. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
3. The following assessments will be completed (the CMAI and NPI-AA should be 
administered before the CGIS-Agitation and CGIC-Agitation):
•
CMAI
•
NPI-AA
•
CGIS-Agitation
•
CGIC-Agitation
4. Register study visit in IWRS and a blister card kit number will be assigned to patient 
(2-week blister card).
5. Unused study drug will be accounted for compliance, and a new blister card will be 
dispensed (2-week blister card).
6. Patient’s Diary Card will be reviewed for compliance and returned to the patient. 
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study drug twice-daily (1 capsule of 
study drug from the top row [AM] of blister card in the morning and 1 capsule of study drug 
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 drug and the patient’s Diary Card at each study visit. For the next scheduled 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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visit (Visit 7, Day 71), caregivers will be advised to administer the morning dose of study drug to 
the patient prior to the clinic appointment and note the time of dosing.
A CMAI caregiver diary will be provided to be used by the caregiver to support reporting of 
behaviors during the CMAI interview process.
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
9.1.8.
Visit 7 (Day 71 ± 3-day window)
Visit 7 (Day 71) should occur in the morning. The morning dose of study drug can be 
administered at home any time before the clinical visit; the time of dosing should be noted by the 
patient/caregiver.
The following procedures will be performed at Visit 7:
1. Vital signs will be measured and recorded.
2. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
3. A blood sample will be collected for PK assessments (at any time during this visit).
4. The following assessments will be completed (the CMAI and NPI should be administered 
before the CGIS-Agitation and CGIC-Agitation):
•
CMAI
•
NPI
•
CGIS-Agitation
•
CGIC-Agitation
5. Register study visit in IWRS and a blister card kit number will be assigned to patient 
(2-week blister card).
6. Unused study drug will be accounted for compliance, and a new blister card will be 
dispensed (2-week blister card). 
7. Patient’s Diary Card will be reviewed for compliance and returned to the patient. 
Patient/Caregiver Instruction
Caregivers will be instructed to administer to the patient the study drug twice-daily (1 capsule of 
study drug from the top row [AM] of blister card in the morning and 1 capsule of study drug 
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 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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any unused study drug and patient’s Diary Card at each study visit. For the next scheduled visit 
(Visit 8, Day 85/ET), caregivers will be advised to administer the morning dose of study drug to 
the patient prior to the clinic appointment and note the time of dosing.
A CMAI caregiver diary will be provided to be used by the caregiver to support reporting of 
behaviors during the CMAI interview process.
Caregivers will be queried at the end of each visit to be certain they understand what is required 
of them.
9.1.9.
Visit 8 (Day 85 ± 3-day window) / Early Termination
Visit 8 (Day 85/ET) should occur in the morning. The morning dose of study drug can be 
administered at home any time prior to the clinic visit; the time of dosing should be noted by the 
patient/caregiver.
Patients who withdraw prior to study completion are required to complete study procedures as 
listed for Visit 8/ET within 48 hours of the last dose of study drug.
The following procedures will be performed at Visit 8 (or ET):
1. Vital signs will be measured and recorded.
2. Weight will be measured and recorded.
3. Physical and neurological examination will be performed.
4. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
5. A resting 12-lead ECG will be performed (any time during this visit).
6. A blood and urine specimen will be collected for safety laboratory assessments.
7. A urine pregnancy test will be performed for women of childbearing potential only 
(Section 8.1.7).
8. The following assessments will be completed (the CMAI and NPI should be administered 
before the CGIS-Agitation and CGIC-Agitation):
•
CMAI
•
NPI
•
CGIS-Agitation
•
CGIC-Agitation
•
EQ-5D-5L
•
RUD-Lite
•
MMSE
•
ESS (only for patients with an MMSE score of ≥ 10 at Baseline)
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•
S-STS
9. Register study visit in IWRS.
10. Any unused study drug will be returned and accounted for compliance.
11. Patient’s Diary Card will be reviewed for compliance.
12. 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 drug.
13. If ET, site staff will access CTSdatabase, enter the patient Study ID and nature of the last 
contact (ie, early terminated).
Caregivers and patients will be instructed to return to the clinic for a Follow-up visit 30 days 
after the last dose of study drug.
9.1.10.
Follow-up Visit (30 days post last dose; + 7-day window)
The Follow-up visit should occur 30 days (+ 7-day window) after the last dose of study drug. 
The following procedures will be performed:
1. The caregiver will be queried regarding AEs, concomitant medications (including OTC, 
vitamins, and supplements), nondrug therapies, and any nonpharmacological 
interventions for the treatment of agitation.
2. The following assessments will be completed:
•
CMAI (completed first)
•
CGIS-Agitation
3. Site staff will access the CTSdatabase and enter the patient Study ID and nature of the 
last contact (ie, completed study).
9.2.
End of Trial
The end of the trial is defined as the “Last Patient Last Visit”, which is the date on which the last 
patient has his or her last visit (ie, the Follow-up visit) or assessment, either for therapeutic or 
follow-up purposes.
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16.1.1 Protocol and Protocol Amendments
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10.
STATISTICS
10.1.
Sample Size Calculations
The planned sample size for this trial is approximately 750 randomized patients. Statistical 
assumptions and additional details are provided in the SAP. 
10.2.
Analysis Populations
The following analysis population are defined for this study:
•
Enrolled: all patients enrolled in this study
•
Randomized: all patients who are randomized into this study
•
Safety: all patients who are randomized in this study and take at least one dose of 
study drug
•
Efficacy: all patients in the randomized population who take at least 1 dose of study 
drug, have a baseline CMAI total score, and at least 1 postbaseline evaluation for the 
CMAI total score.
In general, baseline of an efficacy endpoint is defined as the last observation of the endpoint 
before the patient is randomized.
The core dataset for all efficacy analyses is based on the ITT population, which is defined in the 
efficacy analysis set above. As will be described below, in order to handle missing data and 
restrictions imposed by different types of analyses (eg, change from baseline analysis), datasets 
derived from the ITT population will be used for the efficacy analyses.
10.3.
Handling of Missing Data
In general, missing data will be handled by analysis of mixed-effect model repeated measures 
(MMRM) methodology based on observed-case (OC) data from protocol specified visits in the 
ITT population under the assumption of missing at random. Details of sensitivity analyses under 
the assumption of missing data being missing not at random (MNAR) will be provided in the 
SAP as well as additional sensitivity analyses, as applicable.
The OC dataset consists of actual observations recorded at each visit during the double-blind 
treatment period, and no missing data will be imputed.
10.4.
Efficacy Analysis
10.4.1.
Primary Efficacy Endpoint Analysis
The primary efficacy endpoint is the change from baseline to the end of the efficacy period in the 
CMAI total score. The change from baseline to the end of the efficacy period in the CMAI total 
score will be analyzed using a MMRM analysis with an unstructured variance covariance 
structure (UN). The model will include fixed class effect terms for treatment, study site, baseline 
concomitant antipsychotic use (yes/no), visit week, and an interaction term of treatment by visit 
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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week, and will include the interaction term of baseline values of the CMAI total score and 
NPI-AA score by visit week as a covariate. All scheduled visits after baseline during the 
double-blind treatment period will be included in the model.
Complete details of the planned statistical analysis will be presented in the SAP. Details of 
sensitivity analyses for MNAR, as well as additional sensitivity analyses will be prespecified in 
the SAP.
10.4.2.
Key Secondary Analysis 
The key secondary efficacy variable is the change from baseline to end of efficacy period in the 
CGI-S score, as related to agitation. It will be analyzed by the same statistical methodology 
specified for the analysis of the primary efficacy variable. The procedure to control the overall 
type I error rate for this key secondary efficacy analysis will be described in the SAP.
10.4.3.
Other Efficacy Endpoint Analysis
Other efficacy variables include the following:
•
Change from baseline to each study visit in efficacy period in CMAI Total score 
•
Change from baseline to each study visit in efficacy period in CGIS-Agitation score 
•
CGIC-Agitation score at each study visit in the efficacy period
•
Change from baseline to each study visit in efficacy period in NPI-AA score 
•
Change from baseline to each study visit in efficacy period in NPI total score 
•
CMAI Response Rate at each study visit in efficacy period, where response is defined 
as ≥ 30% reduction in CMAI Total Score from baseline 
•
CMAI Response Rate at each study visit in efficacy period, where response is defined 
as ≥ 50% reduction in CMAI Total Score from baseline 
•
Change from baseline to each study visit in efficacy period in the EQ-5D-5L total 
score 
•
Change from baseline to each study visit in efficacy period in the RUD-Lite
Change from baseline will be evaluated using the same MMRM model described in the primary 
analysis.
Change from baseline for the endpoints with one postbaseline assessment will be evaluated using 
analysis of covariance (ANCOVA) with baseline value, study site and baseline concomitant 
antipsychotic use (yes/no) as a covariate and treatment as main factor.
The response variables will be evaluated by the Cochran-Mantel-Haenszel (CMH) General 
Association Test controlling, in last-observation-carried-forward (LOCF) analyses, for study site 
and baseline concomitant antipsychotic use (yes/no). The OC analysis will not control for 
stratification factors.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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The CGIC-Agitation score will be evaluated by the Cochran–Mantel–Haenszel row mean score 
differ test (van Eltern), controlling for study site and baseline concomitant antipsychotic use 
(yes/no) in the LOCF analysis. The OC analysis will not control for stratification factors.
Further details and analysis methods will be described in the SAP.
10.4.4.
Control of Experiment-wise Type 1 Error
Control of experiment-wise Type 1 error is described in the SAP.
10.4.5.
Other Efficacy Endpoint Analyses
Additional analyses of efficacy endpoints are described in the SAP.
10.5.
Interim Analysis
One interim analysis may be performed; the details of the interim analysis will be provided in an 
interim analysis plan (IAP).
10.6.
Analysis of Demographic and Baseline Characteristics
Demographic characteristics and disease severity at baseline will be summarized by descriptive 
statistics, eg, proportion, mean, median, standard deviation, and minimum and maximum values.
10.7.
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, ECGs, 
and physical and neurological examination. In addition, data from the following safety scales 
will be evaluated: MMSE, ESS, and S-STS. Safety analysis will be conducted based on the 
Safety Population. In general, baseline of a safety variable is defined as the last observation of 
the variable before taking the first dose of study drug, unless specified otherwise. Prospectively 
defined criteria will be used to identify potentially clinically relevant abnormal values for clinical 
laboratory tests, vital signs, ECGs. Details of safety analyses will be provided in the SAP.
10.7.1.
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term. The incidence of the following events will be summarized by 
treatment group:
•
TEAEs
•
TEAEs by severity
•
TEAEs potentially causally related to the study drug
•
TEAEs with an outcome of death
•
Serious TEAEs
•
TEAEs leading to discontinuation of the study drug
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The above summaries will also be prepared for TEAEs potentially causally related to the study 
drug.
10.7.2.
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory measurements 
will be provided. In addition, the incidence of potentially clinically relevant values identified 
using prospectively defined criteria for laboratory tests will be summarized.
10.7.3.
Physical and Neurological Examination and Vital Sign Data
Physical and neurological examination findings will be listed by patient. Potentially clinically 
relevant results in vital signs and body weight will also be summarized. Summary statistics for 
change from baseline in vital signs will be provided.
10.7.4.
Electrocardiogram Data
Mean change from baseline will be summarized by treatment group and by visit. Incidence of 
clinically relevant changes will be calculated for ECG parameters and summarized by treatment 
group and by visit.
The analysis of QT and corrected QT interval (QTc) data from 3 consecutive complexes 
(representing 3 consecutive heart beats) will be measured to determine average values. The 
following QT corrections will be used:
•
QTcF is the length of the QT interval corrected for heart rate by the Fridericia’s 
formula:  QTcF = QT/(RR)0.33
Results will be summarized by visit. 
10.7.5.
Other Safety Data
Change from baseline in scores for the MMSE and ESS will be evaluated using ANCOVA with 
baseline value as a covariate and treatment as main factors. The analyses will be based on the OC 
and LOCF datasets of the Safety Population.
The suicidality (eg, S-STS) will be summarized by treatment group based on the OC dataset of 
the Safety Population. Details will be described in SAP.
10.7.6.
Data and Safety Monitoring Board
The Sponsor will appoint a Data and Safety Monitoring Board (DSMB) for the periodic review 
of available study data.
The DSMB is an independent group of experts that advises the sponsor and the study 
Investigators. The members of the DSMB serve in an individual capacity and provide their 
expertise and recommendations. The primary responsibilities of the DSMB are to 
(1) periodically review and evaluate the accumulated study data for participant safety, study 
conduct and progress, and (2) make recommendations to the sponsor concerning the 
continuation, modification, or termination of the study.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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The DSMB considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.
The DSMB is responsible for defining its deliberative processes, including event triggers that 
would call for an unscheduled review, stopping guidelines, unmasking, and voting procedures 
prior to initiating any data review. The DSMB is also responsible for maintaining the 
confidentiality of its internal discussions and activities as well as the contents of reports provided 
to it.
10.8.
Other Analyses
10.8.1.
Pharmacokinetic Analysis
No PK analysis is planned, as only sparse samples will be obtained. Plasma concentrations of 
d6-DM, its metabolites d3-DX and d3-3-MM, and Q will be summarized using descriptive 
statistics by dose and timepoint. Urine concentrations of d6-DM and its metabolite d3-DX will 
be summarized using descriptive statistics by dose and timepoint.
10.8.2.
Pharmacodynamic Analysis
No pharmacodynamic (PD) analysis is planned.
10.8.3.
Pharmacokinetic/Pharmacodynamic Analysis
A population or PK/PD modeling may be performed using the data from this study and other 
studies and would be reported separately.
10.8.4.
Pharmacogenomic Analysis
CYP2D6 genotype and predicted phenotype will be listed for all patients by treatment group.
10.8.5.
Exploratory Endpoint Analysis
Exploratory endpoint analysis will be described in the SAP.
Abbreviated Clinical Study Report 20-AVP-786-307
16.1.1 Protocol and Protocol Amendments
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11.
ETHICS
11.1.
Ethical Conduct of the Study
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and Council for International Organizations of Medical Science 
(CIOMS); and will be consistent with GCP, ICH Guidelines, and the United States (US) Food 
and Drug Administration (FDA) CFR (21 CFR Parts 50 and 56) for the protection of the rights 
and welfare of human patients participating in biomedical research, and the applicable regulatory 
requirements.
11.2.
Institutional Review Board - Ethics Review
All Institutional Review Boards/Independent Ethics Committee (IRBs/IECs/ECs) must meet the 
requirements as described in Part 56, Title 21 of the Code of Federal Regulations (CFR) and 
conform to local laws and customs where appropriate. Written IRB/IEC/EC approval for the 
protocol and the signed ICF must be obtained and transmitted to the Sponsor or its representative 
before the study can be initiated. 
The protocol, the protocol amendments, and the sample ICF must be reviewed and approved by 
an IRB/IEC/EC of the participating study center in accordance with the CFR, the International 
Conference on Harmonisation (ICH), and Good Clinical Practice (GCP) before initiation of the 
study at their respective center. All protocol amendments and any changes to the ICF that 
occurred during the study must be approved by the Sponsor and the IRB/IEC/EC.
The Investigator will ensure that this study is conducted in full conformance with local laws and 
according to National and State laws of the US (Investigator Responsibilities 57 and the World 
Medical Association Declaration of Helsinki). The Principal Investigator is responsible for 
informing the IRB/IEC/EC of any amendment to the protocol in accordance with local 
requirements. In addition, the IRB/IEC/EC must approve all advertising used to recruit patients 
for the study. The protocol must be re-approved by the IRB/IEC/EC upon receipt of amendments 
and annually, as local regulations require.
The Principal Investigator is also responsible for providing the IRB/IEC/EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the study drug. 
The Sponsor will provide this information to the PI.
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC/EC according to local regulations and guidelines.
11.3.
Written Informed Consent
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 as determined by local regulations. For patients who 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 
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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 drug. 
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.
The Investigators or designee will also explain the IRB/IEC/EC-approved Subject Database 
Authorization to the patient and witness the signature. All participants will also be informed that 
their medical records will be kept confidential except for review by the Sponsor or its 
representatives, the US FDA, or other regulatory agencies if applicable.
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16.1.1 Protocol and Protocol Amendments
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12.
QUALITY CONTROL AND QUALITY ASSURANCE
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.
12.1.
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.
12.2.
Study 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. 
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/IEC/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.
12.3.
Direct Access to Source Data/Documents for Audits and 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 data may be by direct 
inspection of source documents (where permitted by law) or through an interview exchange.
The inspector from the regulatory authority will be especially interested in the following items:
•
Visits from the sponsor’s representatives
•
IRB/IEC/EC approval(s)
•
Study drug accountability
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•
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/IEC/EC and the sponsor
•
Record retention
The sponsor will be available to help investigators prepare for an inspection.
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13.
DATA HANDLING AND RECORDKEEPING
13.1.
Data Management and Collection
The sponsor or designated representative (eg, contract research organization) 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.
Source documents and source data will be captured electronically (where permitted by local 
regulation) in this trial and will meet the same fundamental elements of data quality (eg, 
attributable, legible, contemporaneous, original, and accurate) as paper records. These data will 
be collected into a system that is fully validated according to 21 CFR Part 11. Changes to the 
data will be captured by an automatic audit trail.
Information to be originally captured and reviewed electronically shall include details of the 
subject visit and the protocol required assessments performed as a part of these visits, medical 
history, AEs, and concomitant medications. Because this trial is using an electronic source record 
as the original point of data capture, there is no additional data entry step for the trial site for data 
collected directly into the application, rather, the electronic source record directly populates the 
trial database.
Some data may be captured via paper and then entered into the eSource system. These and any 
other data treated in this manner will be source data verified per the monitoring plan and the 
location of the source data (ie, eSource, paper, or a local electronic system) will be documented 
before the trial start. Any changes to information in paper source documents will be initialed and 
dated on the day the change is made by a trial site staff member authorized to make the change. 
Changes will be made by striking a single line through erroneous data (so as not to obliterate the 
original data), and clearly entering the correct data (eg, wrong data right data). If the reason for 
the change is not apparent, a brief explanation for the change will be written in the source 
documentation by the investigator or their designee.
Another exception will be safety laboratory [or central ECG data], where the official source 
documentation will be considered the report issued by the analyzing laboratory.
Designated trial site staff will not be given access to the electronic source system until they have 
been appropriately trained. 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.
Remote monitoring of the original electronic source records will take place; however, on site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
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adherence, to assess trial site operational capabilities and to perform other monitoring activities 
that cannot be performed remotely.
The clinical monitoring staff will perform source data verification of the data recorded in the 
EDC system 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 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.
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate. After database lock, the investigator will receive an 
electronic copy of the subject data. 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.
13.2.
Source Data
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents will include but are not limited to medical records, electronic 
data, logs, and recorded data from automated instruments or applications.
Data will 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’ data to be monitored.
13.3.
Retention of Records
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, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, 
SAE forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (eg, letters, meeting minutes, telephone call reports). 
The records should be retained by the Investigator according to International Conference on 
Harmonization standards, local regulations, or as specified in the Clinical Trial Agreement, 
whichever is longer.
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, 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.
13.4.
Confidentiality of Study Documents and Patient Records
All information generated in this trial will be considered confidential and will not be disclosed to 
anyone not directly concerned with the trial without the sponsor’s prior written permission. 
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Subject confidentiality requirements of the region(s) where the trial is conducted will be met. 
However, authorized regulatory officials and sponsor personnel (or their representatives) may be 
allowed full access to inspect and copy the records, consistent with local requirements. All IMPs, 
subject bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol, unless otherwise agreed to in writing by the sponsor.
Subjects will be identified only by unique subject ID. If further subject identification is required, 
subjects’ full names may be made known to a regulatory agency or other authorized officials if 
necessary, subject to local regulations.
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.
13.5.
Reports
At the completion of the study, the investigator shall provide the sponsor with an adequate report 
shortly after completion of the investigator's participation in the study as described in CFR 
Title 21, Part 312.64.
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14.
CRITERIA FOR STUDY TERMINATION
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.
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15.
PUBLICATION POLICY
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.
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16.1.1 Protocol and Protocol Amendments
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16.
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54. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for 
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Abbreviated Clinical Study Report 20-AVP-786-307
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Abbreviated Clinical Study Report 20-AVP-786-307
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Abbreviated Clinical Study Report 20-AVP-786-307
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Abbreviated Clinical Study Report 20-AVP-786-307
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