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

 
AVANIR PHARMACEUTICALS, INC. 
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PROTOCOL TITLE: 
A Phase 3, multicenter, randomized, double-blind, placebo-controlled, sequential parallel 
comparison design (SPCD) study to assess the efficacy, safety, and tolerability of AVP-786 
(deuterated [d6]-dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the 
treatment of agitation in patients with dementia of the Alzheimer’s type. 
Protocol: 
15-AVP-786-301-Amendment 3
IND:124099 
Sponsor: 
Avanir Pharmaceuticals, Inc. 
Date: 16 May 2016 
Drug: 
AVP-786 (deuterated [d6]-dextromethorphan 
hydrobromide [d6-DM; INN: deudextromethorphan]/ 
quinidine sulfate [Q]) 
Version: 4.0 
Medical Monitor:  
 
Phone:  
 
Fax:  
 
Avanir Pharmaceuticals, Inc. 
30 Enterprise, Suite 400 
Aliso Viejo, California  92656 
Study Monitor:  
 
Phone:  
 
Fax:  
 
Avanir Pharmaceuticals, Inc. 
30 Enterprise, Suite 400 
Aliso Viejo, California  92656 
AVANIR PHARMACEUTICALS, INC. 
30 Enterprise, Suite 400 
Aliso Viejo, California  92656 
Phone:  (949) 389-6700    Fax:  (949) 643-6800 
NCT Number: NCT02442765
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov

 
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Protocol 15-AVP-786-301 
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Protocol Amendment 3 (Version 4.0) 
Summary of Changes 
Section No. 
Section Title 
Description 
Title Page 
Title page 
The date, version number, and amendment number were changed to reflect 
date of approval, Version 4.0, Amendment 3. 
Updated Medical Monitor and contact information. 
Study 
Synopsis 
Study Population 
Clarified that the study centers will be in North America. 
Assessments and Visits 
Included an additional visit at Day 15 (Visit 2.1). 
Response Measures 
Revised the primary measure to Cohen-Mansfield Agitation Inventory 
(CMAI) and moved Agitation/Aggression domain of the Neuropsychiatric 
Inventory (NPI) to secondary measures.   
Specified that the CMAI, NPI, mADCS-CGIC-Agitation, and CGIS-
Agitation scales must be administered by the same rater. 
Added the Epworth Sleepiness Scale (ESS) as a safety assessment. 
Efficacy Analyses 
Revised the wording on primary efficacy endpoint to reflect CMAI instead 
of Agitation/Aggression domain of the NPI.  
Included the Agitation/Aggression domain of the NPI in the secondary 
analyses. 
Figure 1 
Study Schematic 
Included an additional visit at Day 15 (Visit 2.1). 
Table 1 
•
Added Visit 2.1 (Day 15, Week 2) with the following assessment at this 
visit: vital signs, ECG, AEs, prior and concomitant: medications,
nondrug therapies, and nonpharmacological interventions for agitation,
CMAI, NPI-Agitation/Aggression domain, S-STS, drug administration,
and review and return of unused medication and diary card.
•
Clarified that information on nondrug therapies will be collected at all
visits and also included data collection on concomitant
nonpharmacological interventions for agitation.
•
Added safety laboratory procedures at Day 22 (Visit 3) and Day 64
(Visit 5) and HbA1c test at the Screening Visit and Visit 6.
•
Added ESS at Baseline (Day 1), Day 43 (Visit 4), and Day 85 (Visit 6).
•
Specified that the screening period may be extended after discussion
with and approval by the medical monitor.
•
Clarified that the following scales MUST be administered by the same
rater:  CMAI, NPI, mADCS-CGIC-Agitation, and mCGIS-Agitation.
•
Added that the study medication can be administered at home at Visit 2
and Visit 2.1 if the visit will occur within 2 hours of dosing.

 
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Section No. 
Section Title 
Description 
3 
Study Design 
Revised number of visits to 8 scheduled clinic visits with the new visit 
occurring on Day 15 (Visit 2.1).  Clarified that the study centers will be in 
North America. Specified that Screening will occur within 4 weeks prior to 
randomization. 
5.1.6 
Study Medication 
Administration 
Specified that, for Visits 2 (Day 8) and 2.1 (Day 15), patients/caregivers 
should be advised to take the morning dose within 2 hours of the clinic 
appointment and note the time of dosing. 
5.4 
Patient Compliance 
Specified that patients should bring their unused medication and Diary Card 
on Visit 2.1 (Day 15). 
5.5.1 
 
 
 
5.5.4 
Nondrug Therapies 
Clarified that information on nondrug therapies will be collected. 
5.5.5 
Nonpharmacological 
Interventions for the 
Treatment of Agitation 
Added that information will be collected on any nonpharmacological 
interventions that were used for agitation prior to enrollment or used 
concomitantly during the study.  
6.1 
Efficacy 
Included that whenever possible, each patient and caregiver should have the 
rating scales administered by the same raters throughout the study, for 
consistency of ratings and that the following scales MUST be administered 
by the same rater at each visit:  CMAI, NPI, mADCS-CGIC-Agitation and 
CGIS-Agitation.  
6.1.1 
Cohen-Mansfield 
Agitation Inventory 
(CMAI) 
Revised to indicate that the CMAI is the primary efficacy measure.  
Clarified that the long-form version will be used.  Added CMAI assessment 
at Day 15 (Visit 2.1).  Clarified that the scale MUST be administered by the 
same rater at all applicable visits. 
6.1.2 
Neuropsychiatric 
Inventory (NPI) 
Added NPI-Agitation/Aggression domain assessment at Day 15 (Visit 2.1).   
Clarified that the scale MUST be administered by the same rater at all 
applicable visits. 
6.1.3 
Clinical Global 
Impression of Severity 
of Illness-Agitation 
(CGIS-Agitation) 
Clarified that the scale MUST be administered by the same rater at all 
applicable visits. 

 
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Section No. 
Section Title 
Description 
6.1.5 
Modified Alzheimer’s 
Disease Cooperative 
Study –Clinical Global 
Impression of Change 
Rating (mADCS-CGIC 
Agitation) 
Clarified that the scale MUST be administered by the same rater at all 
applicable visits. 
6.3.2 
Physical and 
Neurological 
Examinations 
Clarified the assessments involved in physical and neurological 
examinations. 
6.3.3 
Vital Signs 
Included the assessment of orthostatic blood pressure and heart rate. 
6.3.4 
Clinical Laboratory 
Tests 
Added safety laboratory procedures at Day 22 (Visit 3) and Day 64 (Visit 5) 
and HbA1c test at the Screening Visit and Visit 6. 
6.3.7 
Sheehan Suicidality 
Tracking Scale (S-STS) 
Added S-STS assessment at Day 15 (Visit 2.1). 
6.3.10 
Epworth Sleepiness 
Scale (ESS) 
Added this scale as a safety assessment to be performed at Baseline (Day 1), 
Day 43 (Visit 4), and Day 85 (Visit 6). 
6.4 
Schedule of Evaluations 
and Procedures 
Revised the assessments to match the changes made in Table 1 and 
rearranged the order of procedures.  Added patient/caregiver instruction at 
the Baseline Visit, Visit 2 (Day 8) and Visit 2.1(Day 15). 
8.3.1 
Study Endpoints 
Revised the primary endpoint to reflect CMAI instead of 
Agitation/Aggression domain of the NPI.  
Revised the secondary endpoints to include Agitation/Aggression domain of 
NPI and moved CMAI to the primary endpoint. 
8.3.2 
Primary Efficacy 
Analyses 
Revised to reflect the CMAI instead of NPI Agitation/Aggression domain. 
Revised to state that an appropriate measure will be included to control the 
overall type I error and will be specified in the SAP. 
8.3.3 
Secondary Efficacy 
Analyses 
Updated to match changes to study endpoints. 
10 
References  
Added references related to the CMAI 
) and the 
ESS 
). 
11 
Appendices 
 
Overall 
 
Formatting and minor wording modification throughout the document. 

 
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Protocol Amendment 2 (Version 3.0) 
Summary of Changes 
Section Number 
Section Title 
Description 
Title Page 
Title page 
The date, version number, and amendment number were changed to 
reflect date of finalization, Version 3.0, Amendment 2. 
Updated Medical Monitor and contact information. 
Study Synopsis  
Dose Regimen, Stage 2 
Described the criteria and the definition for responders and non-
responders for patients who received placebo in Stage 1. 
 
Secondary Measures and 
Efficacy Analyses 
  
Separated CGIC evaluation for Overall Clinical Status (ADCS-
CGIC-Overall) from the evaluation for agitation syndrome 
(mADCS-CGIC-Agitation). 
Removed the EQ-5D-5L scale.  
Table 1 
 
• Specified that ECG should be performed in triplicate at Screening 
• Added CMAI assessment at  Screening, Baseline, Visits 2, 3, 4, 
5, and 6 
• Separated the ADCS-CGIC to ADCS-CGIC-Overall and 
mADCS-CGIC-Agitation, both of which are assessed only at 
Visits 4 and 6 with baseline evaluations at the Baseline visit 
• Revised the NPI assessment at Visit 2 to only the assessment of 
Agitation/Aggression domain 
• Deleted the following assessments at Visits 3 and 5, ZBI, PGIC, 
ADCS-CGIC-Overall, and mADCS-CGIC-Agitation 
• Deleted the EQ-5D-5L at all visits 
• Added weight assessment at visit 6 
 
3 
Study Design 
4.1 
Inclusion Criteria 
 
4.2 
Exclusion Criteria 
 
  
5.3.1 
Randomization 
Provided details on the randomization plan for Stage 2.  Specified 
that patients who receive placebo and who drop out early in Stage 1 
will also be assigned a re-randomization treatment. 
5.5 
 
 
 
 
 
 
 
 

 
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Section Number 
Section Title 
Description 
. 
5.5.1 
 
 
 
 
 
5.5.3 
 
 
 
 
 
6.1.1 
NPI 
Revised the assessment of the NPI to only Agitation/Aggression 
domain at Visit 2.  Revised the NPI recall period to 2 weeks for all 
the visits. 
6.1.2 (new) 
CMAI 
Added background on the CMAI and frequency of assessment.   
 
6.1.3 
CGIS-Agitation 
Removed the CGIS assessment of overall clinical status.  The CGIS 
will be used to only assess severity of Agitation.  
6.1.4 
ADCS-CGIC-Overall 
Separated and clarified the terminology for the scale that assesses 
the impression of change in overall clinical status (ADCS-CGIC-
Overall).  Revised the frequency of assessment to only Visits 4 and 
6, with a baseline evaluation at the Baseline visit. 
6.1.5 
mADCS-CGIC-Agitation 
Separated and clarified the terminology for the scale that assesses 
the impression of change in agitation (mADCS-CGIC-Agitation).  
Revised the frequency of assessment to only Visits 4 and 6, with a 
baseline evaluation at the Baseline visit. 
6.1.6 
ZBI 
Added a description of the scoring of ZBI and removed assessment 
of ZBI at Visits 3 and 5. 
6.1.7 
PGIC 
Removed assessment of PGIC at Visits 3 and 5. 
6.1.11 (old) 
EQ-5D-5L 
Deleted the section on EQ-5D-5L as it will not be assessed at any 
visit. 
6.3.3 
Vital Signs 
Clarified that vital signs should be performed after 5 minutes of 
resting. 
6.3.6 
Electrocardiograms 
Specified that ECGs will be performed in triplicate at Screening 
6.4.1 
Description of Study 
Procedures 
Revised the assessments to match the changes made in the 
Schedule of Events and Procedures (Table 1). 
8.3.1 
Study Endpoints 
 
 
8.3.3 
Secondary Efficacy 
Analyses 
Deleted the detailed description of the gate keeping procedure used 
to analyze secondary endpoints, as the procedure will be described 
appropriately in the Statistical Analysis Plan (SAP). 
10 
References  
Added 2 references related to the CMAI: 
 
 

 
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Section Number 
Section Title 
Description 
11 
Appendices 
 
 
 
 
 
Overall 
 
Formatting and minor wording modification throughout the 
document. 

 
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Protocol Amendment 1 (Version 2.0) 
Summary of Changes 
Section Number 
Section Title 
Description 
Title Page 
Title page 
The date, version number, and amendment number were changed to 
reflect date of finalization, Version 2.0, Amendment 1. 
Study Synopsis 
and 8.3 
Secondary Measures and 
Efficacy Analyses 
Clarified wording to specify that the secondary measure is the 
Caregiver Distress score of the NPI Agitation/Aggression domain. 
Table 1 
Schedule of Evaluations 
and Visits 
Renumbered the footnotes and deleted footnote 6 in Version 1.0 
that specified that only inclusion/exclusion criteria from the 
protocol eligibility form need to be reviewed at baseline. 
Revised footnote 10 and 11 of current version to specify that the 
EQ-5D-5L, DEMQOL, and ADAS-COG should be performed by 
patients with an MMSE score of ≥ 10 ‘at baseline’ instead of ‘at 
that visit’. 
Added footnote (14) that thyroid function tests (TSH, and reflex T3 
and T4 if TSH is abnormal) should be performed at the Screening 
Visit. 
4.2 
Exclusion Criteria 
 
 
5.1.6 
Study Medication 
Administration 
Clarified that study medication should be administered to the 
patient by the caregiver, family member, nursing home staff, or 
self-administered with supervision and that the time the patient 
takes each dose of medication should be recorded in the diary card. 
6.1.3 
Alzheimer’s Disease 
Cooperative Study - 
Clinical Global 
Impression of Change 
Rating (ADCS-CGIC) 
Clarified that at Day 22 (Visit 3) the ADCS-CGIC will be 
completed to assess change from the Baseline visit (Day 1) and at 
Day 64 (Visit 5) it will be completed to assess change from Day 43 
(Visit 4) and change from the Baseline visit (Day 1). 
6.1.5 
Patient Global 
Impression of Change 
(PGIC) 
Deleted the statement on the reference point from which the change 
in PGIC will be assessed for each visit. 
6.1.6 
Dementia Quality of Life 
(DEMQOL) 
Clarified that the DEMQOL is a 28-item questionnaire and should 
be used for patients with MMSE ≥10 at the ‘Baseline visit’. 
6.1.7 
Alzheimer’s Disease 
Assessment Scale-
Cognitive Subscale 
(ADAS-cog) 
Revised to specify that ADAS-cog will be assessed for patients 
with an MMSE score of ≥ 10 at the Baseline visit instead of a score 
of ≥ 10 at that visit. 
6.1.11 
EuroQol 5-Dimension 
5-level (EQ-5D-5L) 
Revised to specify that the patient version will be rated only by 
patients with an MMSE score of ≥10 at the Baseline visit instead of 
a score of ≥10 at that visit. 

 
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Section Number 
Section Title 
Description 
6.3.1.3 
Reporting 
Clarified that a death occurring during the study, or which comes to 
the attention of the investigator within ‘30 days’ (instead of 
4 weeks) after stopping the treatment whether considered treatment-
related or not, must be reported to the sponsor. 
6.3.4 
Clinical Laboratory 
Tests 
Added leucocyte esterase and nitrates in urinalysis 
Added thyroid function tests (TSH, and reflex T3 and T4 tests if 
TSH is abnormal) at Screening visit only. 
6.3.7 
Sheehan Suicidality 
Tracking Scale (S-STS) 
Added that ‘any change in the S-STS score indicating the presence 
of suicidality should be evaluated by the investigator and reported 
to the MM’. 
Overall 
 
Formatting and minor wording modification throughout the 
document. 
 
 

 
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TABLE OF CONTENTS  
Table of Contents .................................................................................................................................... 10 
List of Tables .......................................................................................................................................... 13 
List of Figures ........................................................................................................................................ 13 
List of Abbreviations ............................................................................................................................... 14 
Protocol Agreement ................................................................................................................................. 17 
Study Synopsis ........................................................................................................................................ 18 
1 
Background and Clinical Rationale .............................................................................................. 27 
.................. 27 
.................. 28 
.................. 29 
.................. 29 
2 
Study Objectives ........................................................................................................................... 30 
3 
Study Design ................................................................................................................................. 31 
4 
Study Population ........................................................................................................................... 33 
4.1 
Inclusion Criteria ............................................................................................................. 33 
4.2 
Exclusion Criteria ............................................................................................................ 35 
4.3 
Patient Withdrawal From the Study ................................................................................. 36 
5 
Study Treatments .......................................................................................................................... 38 
5.1 
Treatments Administered ................................................................................................. 38 
5.1.1 Description of Study Medications ........................................................................ 38 
5.1.2 Composition of AVP-786 ..................................................................................... 38 
5.1.3 Packaging ............................................................................................................. 39 
5.1.4 Labeling ................................................................................................................ 39 
5.1.5 Storage of Clinical Supplies ................................................................................. 40 
5.1.6 Study Medication Administration ........................................................................ 40 
5.2 
Accountability of Study Supplies .................................................................................... 40 
5.2.1 Receipt of Supplies ............................................................................................... 40 
5.2.2 Record of Dispensing ........................................................................................... 40 
5.2.3 Unused Supplies ................................................................................................... 41 

 
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5.3 
Methods of Assigning Patients to Treatment Groups ...................................................... 41 
5.3.1 Randomization ...................................................................................................... 41 
5.3.2 Blinding/Masking ................................................................................................. 42 
5.4 
Patient Compliance .......................................................................................................... 42 
5.5 
and Nondrug Therapies ......................................................... 42 
............................................................... 42 
5.5.2 Rescue Medication for the Symptoms of Agitation ............................................. 43 
................................................................. 43 
5.5.4 Nondrug Therapies ............................................................................................... 44 
5.5.5 Nonpharmacological Interventions for the Treatment of Agitation ..................... 44 
6 
Study Assessments and Procedures .............................................................................................. 45 
6.1 
Efficacy ............................................................................................................................ 45 
6.1.1 Cohen-Mansfield Agitation Inventory (CMAI) ................................................... 45 
6.1.2 Neuropsychiatric Inventory (NPI) ........................................................................ 45 
6.1.3 Clinical Global Impression of Severity of Illness-Agitation 
(CGIS-Agitation) .................................................................................................. 46 
6.1.4 Alzheimer’s Disease Cooperative Study - Clinical Global 
Impression of Change Rating (ADCS-CGIC-Overall) ......................................... 46 
6.1.5 Modified Alzheimer’s Disease Cooperative Study - Clinical 
Global Impression of Change Rating (mADCS-CGIC-Agitation) ....................... 47 
6.1.6 Zarit Burden Interview (ZBI) ............................................................................... 47 
6.1.7 Patient Global Impression of Change (PGIC) ...................................................... 48 
6.1.8 Dementia Quality of Life (DEMQOL) ................................................................. 48 
6.1.9 Alzheimer’s disease Assessment Scale-Cognitive Subscale 
(ADAS-cog) ......................................................................................................... 48 
6.1.10 Cornell Scale for Depression in Dementia (CSDD) ............................................. 48 
6.1.11 Resource Utilization in Dementia (RUD) ............................................................ 49 
6.1.12 General Medical Health Rating (GMHR) ............................................................ 49 
6.2 
Pharmacokinetics (PK) .................................................................................................... 49 
6.3 
Safety ............................................................................................................................... 50 
6.3.1 Adverse Events ..................................................................................................... 50 

 
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6.3.2 Physical and Neurological Examinations ............................................................. 52 
6.3.3 Vital Signs ............................................................................................................ 53 
6.3.4 Clinical Laboratory Tests ..................................................................................... 53 
6.3.5 Pregnancy Tests .................................................................................................... 54 
6.3.6 Electrocardiograms ............................................................................................... 54 
6.3.7 Sheehan Suicidality Tracking Scale (S-STS) ....................................................... 54 
6.3.8 Mini-Mental State Examination (MMSE) ............................................................ 54 
6.3.9 Timed Up and Go (TUG) Test ............................................................................. 55 
6.3.10 Epworth Sleepiness Scale (ESS) .......................................................................... 55 
6.4 
Schedule of Evaluations and Procedures ......................................................................... 55 
6.4.1 Description of Study Procedures .......................................................................... 55 
7 
Data Management ......................................................................................................................... 67 
7.1 
Data Collection ................................................................................................................ 67 
8 
Statistical Methods ........................................................................................................................ 68 
8.1 
Analysis Populations ........................................................................................................ 68 
8.2 
Demographic and Baseline Characteristics ..................................................................... 68 
8.3 
Efficacy Analysis ............................................................................................................. 68 
8.3.1 Study Endpoints ................................................................................................... 68 
8.3.2 Primary Efficacy Analysis .................................................................................... 69 
8.3.3 Secondary Efficacy Analyses ............................................................................... 69 
8.4 
PK/PD Analysis ............................................................................................................... 70 
...................................................................................................... 70 
8.6 
Safety Analysis ................................................................................................................ 70 
8.6.1 Adverse Events ..................................................................................................... 70 
8.6.2 Vital Signs and ECGs ........................................................................................... 71 
8.6.3 Clinical Laboratory Values ................................................................................... 71 
8.6.4 Data and Safety Monitoring Board ....................................................................... 71 
8.6.5 Interim Analysis ................................................................................................... 71 
8.7 
Sample Size Calculations ................................................................................................. 71 
9 
Administrative Procedures ............................................................................................................ 73 

 
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9.1 
Institutional Review Board/Ethics Committee Approval ................................................ 73 
9.2 
Informed Consent Form ................................................................................................... 73 
9.3 
Patient’s Diary Card ......................................................................................................... 73 
9.4 
Electronic Case Report Forms ......................................................................................... 74 
9.5 
Quality Assurance ............................................................................................................ 74 
9.5.1 Documentation ..................................................................................................... 74 
9.5.2 Monitoring ............................................................................................................ 74 
9.6 
Record Retention ............................................................................................................. 75 
9.7 
Source Data ...................................................................................................................... 75 
9.8 
Data Handling .................................................................................................................. 75 
9.9 
Laboratory Procedures ..................................................................................................... 75 
9.10 
Guidelines for Good Clinical Practice ............................................................................. 76 
9.11 
Conditions for Amending the Protocol ............................................................................ 76 
9.12 
Conditions for Terminating the Study ............................................................................. 76 
9.13 
Confidentiality of Study Documents and Patient Records ............................................... 76 
9.14 
Reports ............................................................................................................................. 76 
9.15 
Publications ...................................................................................................................... 77 
9.16 
Audits/Inspections ........................................................................................................... 77 
10 
References ..................................................................................................................................... 78 
11 
Appendices .................................................................................................................................... 82 
 
List of Tables 
Table 1 
 Schedule of Evaluations and Visits ................................................................................. 24 
Table 2 
Composition of Investigational Product .......................................................................... 38 
 
List of Figures 
Figure 1 
Study Schematic .............................................................................................................. 23 
Figure 2 
Sample Configuration of Investigational Product Blister Card ....................................... 39 
 
 

 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AA 
Alzheimer’s Association 
AE 
Adverse event 
AD 
Alzheimer’s Disease 
ADAS-cog 
Alzheimer’s Disease Assessment Scale - cognitive subscale 
ADCS 
Alzheimer’s Disease Cooperative Study 
ADCS-CGIC-Overall 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change for 
Overall Clinical Status 
ADWG 
Agitation Definition Work Group 
ALT/SGPT 
Alanine aminotransferase/serum glutamic-pyruvic transaminase 
AST/SGOT 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
AUC 
Area under the concentration-by-time curve 
BID 
Twice daily 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CD-ROM 
Compact disc read-only-memory 
CFR 
Code of Federal Regulations 
Cit AD 
Citalopram study for Agitation in Alzheimer’s disease 
CGIC 
Clinical Global Impression of Change 
CGIS-Agitation 
Clinical Global Impression of Severity of Illness scale for Agitation 
CK 
Creatine kinase 
CMAI 
Cohen-Mansfield Agitation Inventory 
CNS 
Central nervous system 
CRO 
Contract research organization 
CSDD 
Cornell Scale for Depression in Dementia  
d6-DM 
Deuterated (d6)-dextromethorphan hydrobromide 
DEMQOL 
Dementia Quality of Life  
DM 
Dextromethorphan hydrobromide 
DMP 
Data management plan 
DSMB 
Data and Safety Monitoring Board 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders 
ECDEU 
Early Clinical Drug Evaluation Unit 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EP 
European Pharmacopeia 

 
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Abbreviation 
Definition 
ESS 
Epworth Sleepiness Scale 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMHR 
General Medical Health Rating 
GMP 
Good Manufacturing Practice 
HbA1c 
Glycosylated hemoglobin  
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IP 
Investigational product 
IPA 
International Psychogeriatric Association 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward  
mADCS-CGIC-Agitation 
Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of 
Change for Agitation 
MAOI 
Monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MM 
Medical Monitor 
MMRM 
Mixed effects model repeated measures 
MMSE 
Mini-Mental State Examination 
NF 
National Formulary 
NIA 
National Institute on Aging 
NPI 
Neuropsychiatric Inventory 
NPI-NH 
Neuropsychiatric Inventory - Nursing Home version 
OTC 
Over–the-counter 
PGIC 
Patient Global Impression of Change 
pH 
Potential hydrogen 
PK 
Pharmacokinetics 
PR 
The P-R interval from an ECG tracing 
PVC 
Premature ventricular contraction 
Q 
Quinidine sulfate 
QRS 
The Q-R-S complex from an ECG tracing 
QT 
QT interval from an ECG tracing 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using the Fridericia’s formula 

 
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Abbreviation 
Definition 
RBC 
Red blood cell 
RUD 
Resource Utilization in Dementia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
SOC 
System organ class 
SPCD 
Sequential Parallel Comparison Design 
SSRI 
Selective serotonin reuptake inhibitor 
S-STS 
Sheehan Suicidality Tracking Scale 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
TUG 
Timed Up and Go 
USP 
United States Pharmacopoeia 
WBC 
White blood cell 
ZBI 
Zarit Burden Interview 

 
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PROTOCOL AGREEMENT 
Protocol Title: 
A Phase 3, multicenter, randomized, double-blind, placebo-controlled, sequential parallel comparison 
design (SPCD) study to assess the efficacy, safety, and tolerability of AVP-786 (deuterated 
[d6]-dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the treatment of agitation in 
patients with dementia of the Alzheimer’s type. 
Protocol Number: 15-AVP-786-301 (Amendment 3, 16 May 2016) 
This document is a confidential communication of Avanir Pharmaceuticals.  The recipient agrees that no 
unpublished information contained within this document or protocol will be disclosed or published 
without prior consent and written approval from Avanir.  An exception to this agreement may be made for 
the purposes of ethical or regulatory review, in which case this document may be disclosed to an Ethics 
Review Board or any authorized representative of a national authority as required by regulation. 
The signatures of the principal investigator and representative of the sponsor below constitute their 
approval of this protocol and further provide the necessary assurances that: 
1. This study will be conducted according to Good Clinical Practice (GCP) and to all stipulations, as 
specified in both clinical and administrative sections of the protocol including the Declaration of 
Helsinki. 
2. The conduct and results of this study will be kept confidential, and the electronic case report forms 
(eCRFs) and other pertinent data will become the property of Avanir Pharmaceuticals. 
3. The protocol contains all necessary information required to conduct the study, as outlined in the 
protocol, and that the study will not be initiated without the approval of an appropriate Institutional 
Review Board/Ethics Committee (IRB/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 Avanir or its representatives, the U.S. Food and Drug 
Administration (FDA), or other regulatory agencies if applicable. 
 
 
 
 
Principal Investigator Signature 
 
Date 
Principal Investigator Name:_____________________________ 
 
 
 
 
 
 
Avanir Representative Signature 
 
Date 
Avanir Representative: 
 
 
 

 
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STUDY SYNOPSIS 
Title: A Phase 3, multicenter, randomized, double-blind, placebo-controlled, sequential parallel 
comparison design (SPCD) study to assess the efficacy, safety, and tolerability of AVP-786 (deuterated 
[d6]-dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the treatment of agitation in 
patients with dementia of the Alzheimer’s type. 
Study Objectives 
The objectives of the study are to evaluate the efficacy, safety, and tolerability of AVP-786 compared to 
placebo, for the treatment of agitation in patients with dementia of the Alzheimer’s type.   
Study Population 
Number of Patients:  Approximately 380 patients will be enrolled at approximately 60 centers in North 
America. 
Condition/Disease:  Patients with agitation secondary to dementia of the Alzheimer’s type.  The diagnosis 
of probable Alzheimer’s disease will be based on the ‘2011 Diagnostic Guidelines for Alzheimer’s 
Disease’ issued by the National Institute on Aging (NIA)-Alzheimer’s Association (AA) workgroups.1  
Diagnosis of agitation will be based on the provisional consensus definition of agitation in patients with 
cognitive disorders developed by the International Psychogeriatric Association (IPA) Agitation Definition 
Work Group.2   
Key Inclusion Criteria:  Patients with clinically significant, moderate/severe agitation at the time of 
screening and for at least 2 weeks prior to randomization, that interferes with daily routine and for which 
a prescription medication is indicated in the opinion of the investigator.  A Clinical Global Impression of 
Severity of Illness scale for Agitation (CGIS-Agitation) score of ≥ 4 (moderately ill) at screening and 
baseline is required for study participation.  Eligible patients must have a reliable caregiver who is able 
and willing to comply with study procedures, including not administering any prohibited medications 
during the course of the study.   
Key Exclusion Criteria:  Patients with dementia predominantly of the non-Alzheimer’s type (e.g., 
vascular dementia, frontotemporal dementia, Parkinson’s disease, substance-induced dementia) and 
patients with symptoms of agitation that are not secondary to Alzheimer’s disease (e.g., secondary to 
pain, other psychiatric disorder or delirium) are not eligible. 
A complete list of inclusion/exclusion criteria is presented in Section 4 of the study protocol. 
Study Design 
Structure: This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, SPCD study 
comprising 2 stages.  A schematic of the study design is presented in Figure 1. 
Duration: Patients will be enrolled in the study for approximately 16 weeks; with up to 4-week screening 
period and 12-week treatment period.  The treatment period is divided equally into 2 stages of 6 weeks 
each, Stage 1 and Stage 2. 

 
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Study Treatment:  The investigational product is AVP-786 (deuterated [d6]-dextromethorphan 
hydrobromide [d6-DM; INN:deudextromethorphan]/quinidine sulfate [Q]).  Two doses of AVP-786 will 
be evaluated; d6-DM 28 mg/Q 4.9 mg and d6-DM 18 mg/Q 4.9 mg, hereafter referred to as AVP-786-
28/4.9 and AVP-786-18/4.9, respectively.  
Control:  Placebo capsules of identical appearance to study medication will be used as control. 
Randomization/Stratification:  Eligible patients will be randomized into the study in a 
 
(active:active:placebo) ratio to receive either AVP-786-28/4.9 capsules, AVP-786-18/4.9 capsules, or 
matching placebo capsules in Stage 1.  The randomization will be stratified by the Neuropsychiatric 
Inventory (NPI) Agitation/Aggression domain score (≤ 6 vs. > 6), risk assessment for falls (normal/mild 
vs. moderate/severe), and concomitant use of antipsychotic medications (yes vs. no).    
Dose Regimen: Eligible patients will be randomly assigned at the Baseline visit to receive AVP-786 or 
matching placebo capsules.  Study medication will be administered orally twice daily (BID, 1 capsule in 
the morning and 1 capsule in the evening approximately 12 hours apart) throughout the study.  
Stage 1 
• 
Patients randomized to receive AVP-786-28/4.9 will start with AVP-786-18/4.9 once a day in the 
morning and placebo in the evening for the first 7 days of the study.  From Day 8, patients will 
receive AVP-786-18/4.9 BID for 14 days.  From Day 22, patients will receive AVP-786-28/4.9 BID 
for the remaining 3-week duration of Stage 1.  
• 
Patients randomized to receive AVP-786-18/4.9 will start with AVP-786-18/4.9 once a day in the 
morning and placebo in the evening for the first 7 days of the study.  From Day 8, patients will 
receive AVP-786-18/4.9 BID for the remaining 5-week duration of Stage 1. 
• 
Patients randomized to receive placebo will be dosed with placebo BID during Stage 1.  
Stage 2: 
Patients who complete Stage 1 are eligible to participate in Stage 2 of the study.  In Stage 2, patients will 
be assigned to study treatment as follows: 
• 
Patients who received AVP-786 in Stage 1 will continue to receive the same dose of AVP-786 BID 
(either AVP-786-18/4.9 or AVP-786-28/4.9) for the entire 6-week duration of Stage 2. 
• 
Patients who received placebo in Stage 1 will be further stratified into two sub-groups (“responders” 
and “non-responders”) on Visit 4 (Day 43) based on their treatment response.  Patients will be 
considered “responders” if their CGIS-Agitation score is ≤ 3 at Visit 4 (Day 43) and their NPI 
Agitation/Aggression domain score has decreased by ≥ 25% from baseline.  Patients who do not meet 
these criteria will be considered “non-responders”.  Patients within each placebo sub-group will be re-
randomized in a 
 (active:active:placebo) ratio to receive either AVP-786-18/4.9, AVP-786-
28/4.9 capsules, or matching placebo capsules. 
o Patients who are re-randomized to placebo will continue to receive placebo BID for the entire 
6-week duration of Stage 2. 

 
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o Patients who are re-randomized to AVP-786-28/4.9 will receive AVP-786-18/4.9 once a day 
in the morning and placebo in the evening for the first 7 days of Stage 2 (Days 43-49).  From 
Day 50, patients will receive AVP-786-18/4.9 BID for 14 days (Days 50-63).  From Day 64, 
patients will receive AVP-786-28/4.9 BID for the remaining 3 weeks of the study. 
o Patients who are re-randomized to AVP-786-18/4.9 will receive AVP-786-18/4.9 once a day 
in the morning and placebo in the evening for the first 7 days of Stage 2 (Days 43-49).  From 
Day 50, patients will receive AVP-786-18/4.9 BID for the remaining 5 weeks of the study. 
Assessments and Visits  
Patients will attend clinic visits at Screening, Baseline (Day 1), and on Days 8 (Week 1), 15 (Week 2), 
22 (Week 3), 43 (Week 6), 64 (Week 9), and 85 (Week 12).  Safety follow-up phone calls will be made 
on Days 29 (Week 4) and 71 (Week 10).  Study procedures will be performed at each visit as outlined in 
the Schedule of Evaluations and Visits (Table 1).  
Response Measures 
Efficacy  
Primary measure: Primary efficacy will be assessed using the Cohen-Mansfield Agitation Inventory 
(CMAI).  
Secondary measures:  Secondary efficacy measures include: Agitation/Aggression domain of the NPI, 
modified Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change-Agitation 
(mADCS-CGIC-Agitation), NPI-Agitation/Aggression domain Caregiver Distress score, NPI-Aberrant 
Motor Behavior domain, Zarit Burden Interview (ZBI), NPI-Irritability/Lability domain, Patient Global 
Impression of Change (PGIC, rated by caregiver), Dementia Quality of Life (DEMQOL), Cornell Scale 
for Depression in Dementia (CSDD), Resource Utilization in Dementia (RUD), total NPI, ADCS-CGIC-
Overall, CGIS-Agitation, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and 
General Medical Health Rating (GMHR). 
For consistency of rating, assessments should be performed, whenever possible, by the same rater 
throughout the study.  The following scales MUST be administered by the same rater at each visit:  
CMAI, NPI, mADCS-CGIC-Agitation, and CGIS-Agitation. 
Pharmacokinetics 
Plasma concentrations of d6-DM, its metabolites, and Q will be measured. 
Safety and Tolerability  
Safety and tolerability of AVP-786 will be assessed by reported adverse events (AEs), physical and 
neurological examinations, vital signs, clinical laboratory assessments, resting 12-lead electrocardiograms 
(ECGs), Sheehan Suicidality Tracking Scale (S-STS), Mini Mental State Examination (MMSE), Timed 
Up and Go (TUG) test, and the Epworth Sleepiness Scale (ESS).  

 
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Pregnancy tests will be conducted for females of childbearing potential. 
General Statistical Methods and Types of Analyses 
Analysis Populations 
Three analysis populations will be used; modified intent-to-treat (mITT), intent-to-treat (ITT), and safety.  
The mITT population includes all patients randomized in the study who had at least one post-baseline 
efficacy assessment, and will be used for all analyses of efficacy.  Patients in the mITT population will be 
included in the treatment group to which they were randomized regardless of treatment received.  The 
ITT population includes all randomized patients in the study, and will be used for exploratory efficacy 
analyses.  The safety population includes all patients who received study treatment, and will be used for 
all analyses of safety.  Patients will be included in the treatment group based on the actual treatment 
received. 
Efficacy Analyses  
The primary efficacy analysis will be based on the SPCD method.  The primary efficacy endpoint of the 
study is the change from Baseline to Week 6 (Day 43, Stage 1) and from Week 6 to Week 12 (Day 85, 
Stage 2) in the composite CMAI scores.  A weighted test statistics combining treatment effects from 
Stage 1 and 23 will be used.  The treatment effect in each stage will be estimated by using a likelihood-
based linear mixed effects model repeated measures (MMRM) on observed data.  Data from Stage 1 
placebo non-responders who are re-randomized into Stage 2 will be used to estimate the Stage 2 treatment 
effect.  Appropriate procedures to control type I error will be implemented and the details will be 
provided in the Statistical Analysis Plan (SAP).    
Secondary efficacy endpoints include change from Baseline to Week 6 (Day 43, Stage 1) and from 
Week 6 to Week 12 (Day 85, Stage 2) for the following efficacy measures: mADCS-CGIC-Agitation, 
NPI-Agitation/Aggression domain score and Caregiver Distress score, NPI-Aberrant Motor Behavior 
domain, ZBI, NPI-Irritability/Lability domain, PGIC, DEMQOL, CSDD, RUD, total NPI, CGIS-
Agitation, ADCS-CGIC-Overall, ADAS-cog; and change from Baseline to Week 12 for GMHR.   
Safety Analyses 
Safety measures will be summarized by Stage 1, Stage 2, and the 2 stages combined.  
Sample Size Calculation 
Power calculations were performed assuming a bivariate normal distribution for the primary efficacy 
endpoint with AVP-786-28/4.9 (high dose) versus placebo.  
 
 
 
 
 
  
  
 
 
  To control the 

 
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overall type I error rate at 
level, the null hypothesis about the low dose AVP-786-18/4.9 will be 
tested only if the null hypothesis about the high dose is rejected. 

 
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Figure 1 
Study Schematic 
 
Stratification based on Treatment Response
Re-Randomization 
 at Visit 4 (Day 43)*






Placebo

Responders


AVP-786-28/4.9  (d6-DM 28mg /Q 4.9 mg)


M
18/4.9
18/4.9
18/4.9
28/4.9
28/4.9
28/4.9
Placebo
E Placebo
18/4.9
18/4.9
28/4.9
28/4.9
28/4.9
AVP-786-18/4.9 (d6-DM 18mg /Q 4.9 mg)
M
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
E Placebo
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
Placebo
Screening
Non-Responders
AVP-786-28/4.9  (d6-DM 28mg /Q 4.9 mg)
M
18/4.9
18/4.9
18/4.9
28/4.9
28/4.9
28/4.9
E Placebo
18/4.9
18/4.9
28/4.9
28/4.9
28/4.9
AVP-786-18/4.9 (d6-DM 18mg /Q 4.9 mg)
M
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
E Placebo
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
AVP-786-28/4.9  (d6-DM 28mg /Q 4.9 mg)
M
18/4.9
18/4.9
18/4.9
28/4.9
28/4.9
28/4.9
M
28/4.9
28/4.9
28/4.9
28/4.9
28/4.9
28/4.9
E Placebo
18/4.9
18/4.9
28/4.9
28/4.9
28/4.9
E
28/4.9
28/4.9
28/4.9
28/4.9
28/4.9
28/4.9
AVP-786-18/4.9 (d6-DM 18mg /Q 4.9 mg)
M
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
M
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
E Placebo
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
E
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
18/4.9
Period
Stage 2
Visit
Screening
Visit 2
Visit 2.1 Visit 3
Phone
Visit 4*
Visit 5
Phone
Visit 6
Day 
8
22
29
43
64
71
85
Week
Week 2
Week 3
Week 4 Week 5 Week 6
week 7
Week 8
Week 9 Week 10 Week 11 Week 12
Study medication (active or placebo) will be administered as capsules; 1 in the morning and 1  in the evening, approximately 12 hours apart.
     M: Morning Dose (in mg d6-DM/mg Q)
      E: Evening Dose (in mg d6-DM/mg Q)
*: Visit 4 (Day 43) stratification for the placebo arm is based on treatment response criteria followed by Re-Randomization 
.
Week -4
Week 1
Stratification based on the Neuropsychiatric Inventory  
(NPI) Agitation/Agression Domain Score, Risk Assessment 
for Falls, and Concomitant Antipsychotic Medications
Randomization 
at Baseline (Day 1)
Screening
Stage 1
Baseline
-28
1

 
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Table 1 
Schedule of Evaluations and Visits 
Procedure 
Visit: 
Screening1 
Baseline 
Visit 21 Visit 2.11 Visit 31 
Phone 
Call1,2 
Visit 41 
Visit 51 
Phone 
Call1,2 
Visit 61 
/ET3,4 
Study Day: Day -28 to -1 
Day 1 
Day 8 
Day 15 
Day 22 Day 29 
Day 43 
Day 64 Day 71 
Day 85 
End of Study Week: Week -4 to -1 
 
Week 1 Week 2 Week 3 Week 4 Week 6 
Week 9 Week 10 Week 12 
Sign informed consent forms 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility5 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical and neurological examination 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Vital signs and weight 
X 
X6 
 
X 
X 
X 
 
X 
 
X 
 
X6 
ADCS-CGIC-Overall 
 
X7 
 
 
 
 
 
X 
 
 
 
X 
CGIS-Agitation 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
mADCS-CGIC-Agitation 
 
X8 
 
 
 
 
 
X 
 
 
 
X 
Risk assessment for falls (worksheet and TUG test)  
X 
 
 
 
 
 
 
X9 
 
 
 
X9 
ECG  
X10 
X11 
X11 
 
X 
X 
 
X11 
X11 
X 
 
X 
AEs 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Prior and concomitant: medications, nondrug 
therapies, and nonpharmacological interventions 
for agitation 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
MMSE 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
GMHR  
X 
 
 
 
 
 
 
 
 
 
 
X 
CMAI 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
NPI 
X12 
X 
 
X12 
X12 
X 
 
X 
 
X 
 
X 
CSDD 
X 
 
 
 
 
 
 
X 
 
 
 
X 

 
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Procedure 
Visit: 
Screening1 
Baseline 
Visit 21 Visit 2.11 Visit 31 
Phone 
Call1,2 
Visit 41 
Visit 51 
Phone 
Call1,2 
Visit 61 
/ET3,4 
Study Day: Day -28 to -1 
Day 1 
Day 8 
Day 15 
Day 22 Day 29 
Day 43 
Day 64 Day 71 
Day 85 
End of Study Week: Week -4 to -1 
 
Week 1 Week 2 Week 3 Week 4 Week 6 
Week 9 Week 10 Week 12 
ZBI 
 
X 
 
 
 
 
 
X 
 
 
 
X 
DEMQOL13 
 
X 
 
 
 
 
 
X 
 
 
 
X 
ADAS-cog14 
 
X 
 
 
 
 
 
X 
 
 
 
X 
PGIC15 
 
 
 
 
 
 
 
X 
 
 
 
X 
RUD 
 
X 
 
 
 
 
 
X 
 
 
 
X 
ESS 
 
X 
 
 
 
 
 
X 
 
 
 
X 
S-STS 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
Administer morning dose of study medication in 
clinic 
 
 
X 
X16 
X16 
X 
 
 
X 
X 
 
X 
Chemistry, hematology, and urinalysis 
X17 
 
 
 
 
X 
 
 
X 
X 
 
X17 
Urine pregnancy test18 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
PK blood sample  
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug and diary card 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
Review and return unused study medication and 
diary card 
 
 
 
X16 
X16 
X 
 
X 
 
X 
 
X 
ADAS-cog  = Alzheimer's Disease Assessment Scale-cognitive subscale; ADCS-CGIC-Overall = Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change 
for Overall Clinical Status; AE = adverse event; CGIS-Agitation = Clinical Global Impression of Severity of Illness scale for Agitation; CMAI = Cohen-Mansfield Agitation  
Inventory; CSDD  = The Cornell Scale for Depression in Dementia; DEMQOL = Dementia Quality of Life scale; ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; ET = 
early termination; GMHR = General Medical Health Rating; mADCS-CGIC-Agitation = modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change 
for Agitation; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; PGIC = Patient Global Impression of Change rated by the caregiver; PK = 
pharmacokinetics; RUD = Resource Utilization in Dementia; S-STS = Sheehan Suicidality Tracking Scale; TUG = Timed Up and Go; ZBI = Zarit Burden Interview 
Note:  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, NPI, mADCS-CGIC-Agitation, and CGIS-Agitation. 

 
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1 
Study visits have a +/- 3-day window except Screening, Visit 2, and phone calls.  Screening, Visit 2, and phone calls have a +3-day window.  The screening period may be 
extended after discussion with and approval by the medical monitor. 
2 
Phone call should be made to patient/caregiver to collect adverse events and query on concomitant medication use 
3 
Early termination visit for patients who withdraw prior to study completion 
4 
Patients who terminate early from the study or who do not roll over to the extension study (Study 15-AVP-786-303) will receive a safety follow-up phone call 30 days after 
the last dose of study medication 
5 
For each patient, a protocol eligibility form will be completed 
6 
Weight should be measured only at the Baseline Visit and Visit 6  
7 
The ADCS-CGIC-Overall baseline evaluation worksheet should be completed to record baseline information for assessing change at Visits 4 and 6 
8 
The mADCS-CGIC-Agitation baseline evaluation worksheet should be completed to record baseline information for assessing change at Visits 4 and 6  
9 
Only the TUG test should be performed for risk assessment of falls at Visits 4 and 6 
10 
ECG should be performed in triplicate at the Screening visit 
11 
ECG to be performed pre-dose and post-dose 
12 
Only the Agitation/Aggression domain of the NPI should be performed at the Screening Visit,Visit 2, and Visit 2.1   
13 
The proxy version is to be rated by the caregiver.  The non-proxy version is to be rated only by patients with an MMSE score of ≥ 10 at baseline 
14 
ADAS-cog is to be rated only by patients with an MMSE score of ≥ 10 at baseline 
15 
PGIC is to be rated by the caregiver 
16 
The morning dose of study medication can be administered at home if the visit will occur within 2 hours of dosing; the time of dosing should be noted by the 
patient/caregiver.  The blister card and diary card should be returned to the patient/caregiver after reviewing for compliance.  
17 
Thyroid function tests (TSH, and reflex T3 and T4 if TSH is abnormal) should be performed at the Screening Visit.  Glycosylated hemoglobin (HbA1c) test should be 
performed at the Screening Visit and Visit 6. 
18 Urine pregnancy test to be performed for females of child bearing potential only 
 

 
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1 
BACKGROUND AND CLINICAL RATIONALE 
1.1 
 
 

 
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1.2 
 
 
 
  
 

 
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2 
STUDY OBJECTIVES 
The objectives of the study are 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.   

 
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3 
STUDY DESIGN 
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, SPCD study of 12-week 
treatment duration.  The treatment period is divided equally into 2 stages of 6 weeks each, Stage 1 and 
Stage 2. 
Sequence 
Screening 
Stage 1 
Stage 2 
Study Day 
Day -28 to -1 
Day 1 to 42 
Day 43 to 85 
 
There will be 8 scheduled clinic visits including a screening visit, and 2 safety follow-up phone visits in 
this study.  Patients will attend clinic visits at Screening, Baseline (Day 1), and on Days 8 
(Visit 2/Week 1), 15 (Visit 2.1/Week 2), 22 (Visit 3/Week 3), 43 (Visit 4/Week 6), 64 (Visit 5/Week 9), 
and 85 (Visit 6/Week 12).  Safety follow-up phone calls will be made on Days 29 (Week 4) and 
71 (Week 10).  A schematic of the study design is depicted in Figure 1. 
Approximately 380 patients will be enrolled at approximately 60 centers in North America.   
Eligible patients will be randomly assigned at the Baseline visit to receive AVP-786 or matching placebo.  
Study medication will be administered orally twice daily from Day 1 through Day 85.  Patients (or 
caregivers) will self-administer study medication on all study days except on the clinic-visit days when 
patients will be administered their morning dose of study medication at the clinic in the presence of site 
personnel, regardless of the time of day.  Screening will occur within 4 weeks prior to randomization.   
Stage 1 
Following screening procedures for assessment of inclusion and exclusion criteria, eligible patients will 
be randomized into the study in a 
 (active:active:placebo) ratio to receive either AVP-786-28/4.9 
capsules, AVP-786-18/4.9 capsules, or matching placebo capsules.  The randomization will be stratified 
by the NPI Agitation/Aggression domain score (≤ 6 vs. > 6), risk assessment for falls (normal/mild vs. 
moderate/severe), and concomitant use of antipsychotic medications (yes vs. no).  Study medication 
(active or placebo) will be administered orally BID (1 capsule in the morning and 1 capsule in the evening 
approximately 12 hours apart) throughout the treatment period. 
• 
Patients randomized to receive AVP-786-28/4.9 will start with AVP-786-18/4.9 once a day in the 
morning and placebo in the evening for the first 7 days of the study.  From Day 8, patients will 
receive AVP-786-18/4.9 BID for 14 days.  From Day 22, patients will receive AVP-786-28/4.9 BID 
for the remaining 3-week duration of Stage 1.  
• 
Patients randomized to receive AVP-786-18/4.9 will start with AVP-786-18/4.9 once a day in the 
morning and placebo in the evening for the first 7 days of the study.  From Day 8, patients will 
receive AVP-786-18/4.9 BID for the remaining 5-week duration of Stage 1. 
• 
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Stage 2: 
Patients who complete Stage 1 are eligible to participate in the 6-week Stage 2 of the study.  In Stage 2, 
patients will be assigned to study treatment as follows: 
• 
Patients who received AVP-786 in Stage 1 will continue to receive the same dose of AVP-786 BID 
(either AVP-786-28/4.9 or AVP-786-18/4.9) for the entire 6-week duration of Stage 2. 
• 
Patients who received placebo in Stage 1 will be further stratified into two sub-groups (“responders” 
and “non-responders”) on Visit 4 (Day 43) based on their treatment response.  Patients will be 
considered “responders” if 
 
 
 will be considered “non-responders”.   Patients within each placebo sub-group will be 
re-randomized in a 
 (active:active:placebo) ratio to receive either AVP-786-28/4.9 capsules, 
AVP-786-18/4.9 capsules, or matching placebo capsules. 
o Patients who are re-randomized to placebo will continue to receive placebo BID for the entire 
6-week duration of Stage 2. 
o Patients who are re-randomized to AVP-786-28/4.9 will receive AVP-786-18/4.9 once a day 
in the morning and placebo in the evening for the first 7 days of Stage 2 (Days 43-49).  From 
Day 50, patients will receive AVP-786-18/4.9 BID for 14 days (Days 50-63).  From Day 64, 
patients will receive AVP-786-28/4.9 BID for the remaining 3 weeks of the study. 
o Patients who are re-randomized to AVP-786-18/4.9 will receive AVP-786-18/4.9 once a day 
in the morning and placebo in the evening for the first 7 days of Stage 2 (Days 43-49).  From 
Day 50, patients will receive AVP-786-18/4.9 BID for the remaining 5 weeks of the study. 

 
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4 
STUDY POPULATION 
Patients enrolled in this study must have a diagnosis of probable AD and must present with clinically 
meaningful, moderate/severe agitation secondary to AD.  
The diagnosis of probable AD will be based on the ‘2011 Diagnostic Guidelines for Alzheimer’s Disease’ 
issued by the National Institute on Aging (NIA)-Alzheimer’s Association (AA) workgroups.1  These new 
criteria were developed based on the review of the NINCDS–ADRDA criteria.22  Neither AD nor 
agitation should be explainable by delirium, substance use and/or major psychiatric disorders.  
The provisional consensus definition of agitation in patients with cognitive disorders developed by the 
Agitation Definition Work Group (ADWG) from the International Psychogeriatric Association (IPA)2, 
will be used for selecting study patients.  This proposed definition is limited to patients with cognitive 
impairment and requires:  (a) evidence of emotional distress; (b) one of 3 observable types of behaviors-
excessive motor activity, verbal aggression, or physical aggression; (c) that the behavior causes excess 
disability; and (d) that the behaviors cannot be solely attributable to a suboptimal care environment or 
other disorder such as a psychiatric illness, a medical illness, or effects of a substance.  
Eligible patients must have agitation (persistent or frequently recurrent) at the time of study screening and 
for at least 2 weeks prior to randomization and the agitation symptoms must be severe enough such that 
they interfere with daily routine and cause distress to the patient and caregiver for which a prescription 
medication is deemed indicated, in the opinion of the treating physician. 
Agitation will further be assessed using the CGIS-Agitation scale (0-7).  A score of ≥ 4 (moderately ill) at 
screening and baseline are required for study participation. 
Eligible patients are to have otherwise acceptable and stable general health as required by the study 
protocol, and documented by medical history, physical examination, electrocardiogram (ECG), and 
clinical laboratory examinations. 
Eligible patients must have a caregiver who is able and willing to comply with all required study 
procedures, ensuring that the patient attends all study visits and takes the study medication as instructed.  
Caregivers will also be instructed to keep a study diary, to report any changes in patient’s status, 
including adverse events, standard of care setting (e.g., becoming a resident in an assisted living facility), 
and to provide their impression and assessment regarding the investigational treatment.  In order to 
qualify as a reliable informant (i.e., caregiver) capable of assessing changes in the patient’s condition 
during this study, the individual must spend a minimum of 2 hours per day for 4 days per week with the 
study patient.  
4.1 
Inclusion Criteria 
1. 
Males and females 50 to 90 years of age, inclusive at the time of informed consent. 
2. 
Diagnosis of probable AD according to the 2011 NIA-AA working groups criteria.  Either out-
patients or residents of an assisted-living facility or a skilled nursing home. 

 
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3. 
The patient has clinically significant, moderate/severe agitation at the time of screening and for 
at least 2 weeks prior to randomization, that interferes with daily routine and for which a 
prescription medication is indicated, in the opinion of the investigator.   
4. 
The diagnosis of agitation must meet the IPA provisional definition of agitation. 
5. 
CGIS-Agitation score is ≥ 4 (moderately ill) at Screening and Baseline. 
6. 
MMSE score is between 6 and 26 (inclusive) at Screening and Baseline. 
7. 
 
8. 
 
   
9. 
 
 
 
 
10. 
 
 
 
11. 
 
 
 
 
 
 
12. 
 
 
 
 
 
13. 
 
 
 
14. 
 

 
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15. 
 
 
 
16. 
Caregiver must be willing and able to comply with study procedures, including not 
administering any prohibited medications during the course of the study. 
17. 
 
  
 
 
 
4.2 
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 (e.g., vascular dementia, 
frontotemporal dementia, Parkinson’s disease, substance-induced dementia). 
3. 
 
4. 
Patients with myasthenia gravis 
 
5. 
 
 
a. 
 
b. 
 
 
6. 
. 
7. 
 
 
8. 
 
9. 
 
10. 
 

 
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11.
Patients with co-existent clinically significant or unstable systemic diseases that could
confound the interpretation of the safety results of the study (e.g., malignancy [except skin
basal-cell carcinoma or untreated prostate cancer], poorly controlled diabetes, poorly controlled
hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease,
dilated cardiomyopathy, or unstable valvular heart disease). 
12.
13.
14.
15.
16.
4.3 
Patient Withdrawal From the Study 
Patients and caregivers will be advised verbally and in the written ICF that they have the right to 
withdraw from the study at any time without prejudice or loss of benefits to which they are otherwise 
entitled.  The investigator or sponsor may discontinue a patient from the study in the event of an 
intercurrent illness, adverse event, other reasons concerning the health or well-being of the patient, or in 
the case of lack of cooperation, non-compliance, protocol violation, or other administrative reasons.  If a 
patient does not return for a scheduled visit, every effort should be made to contact the patient. 
Regardless of the circumstance, every effort should be made to document patient outcome, if possible.  
The investigator should inquire about the reason for withdrawal, request the caregiver return all unused 
investigational product (IP), and follow-up with the patient regarding any unresolved adverse events.  
 
 
 
Patients who withdraw prior to study completion will be asked to return to the clinic to complete the 
Visit 6 (end of study) assessments.   
If the patient withdraws from the study, and consent is withdrawn by the caregiver and/or patient’s 
representative for disclosure of future information, no further evaluations should be performed, and no 

 
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additional data should be collected.  The sponsor may retain and continue to use any data collected before 
such withdrawal of consent.  Patients who withdraw from the study will not be replaced. 

 
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5 
STUDY TREATMENTS 
5.1 
Treatments Administered 
5.1.1 
Description of Study Medications 
Clinical study medication will be provided as hard, printed, 
, gelatin capsules 
.  Each 
capsule of the study medication contains 1 of the following: 
• 
28 mg of d6-DM and 4.9 mg of Q (USP, EP):  AVP-786-28/4.9 
• 
18 mg of d6-DM and 4.9 mg of Q (USP, EP):  AVP-786-18/4.9 
• 
AVP-786 placebo 
Drug supplies will be provided to the site in double-blind, individual, pre-labeled blister cards.    
All medication used in this study will be prepared, packaged, and labeled in accordance with Good 
Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines, and applicable laws and regulations. 
5.1.2 
Composition of AVP-786 
The qualitative and quantitative compositions of the 2 doses of the IP and the placebo are listed in 
Table 2. 
Table 2 
Composition of Investigational Product 
Ingredient (amounts in mg) 
AVP-786-28/4.9 
AVP-786-18/4.9 
AVP-786 
Placebo 
d6-Dextromethorphan hydrobromide  
28.00 
18.00 
0 
Quinidine sulfate  USP, EP 
4.90 
4.90 
0 
Croscarmellose sodium NF 
Microcrystalline cellulose NF 
Colloidal silicone dioxide NF 
Magnesium stearate NF 
Total  
 capsules (average weight) 
Total 
EP = European Pharmacopoeia; USP = United States Pharmacopoeia; NF = National Formulary 
 

 
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5.1.3 
Packaging 
The investigators will be supplied with pre-labeled, individually pre-packaged and tamper-proof sealed 
blister cards.  Each panel of the blister card (1 week of study medication) consists of 2 rows of blister 
strips, one row for the morning dose and one row for the evening dose (Figure 2).  Each blister card will 
contain 3 panels, providing sufficient study medication for 3 weeks of treatment and an additional 3 days 
of supply (total of 48 capsules).   
Figure 2 
Sample Configuration of Investigational Product Blister Card 
 
 
5.1.4 
Labeling 
All labels will contain protocol number, product name, blister card number, an investigational drug 
warning, and dosage instructions to take 1 capsule in the morning and 1 capsule in the evening, storage 
conditions, and company name.  The blister card label will consist of 2 panels, with 1 detachable panel 
that will be removed and affixed to the study medication Dispensing Log page at the time of dispensing.  
Space is provided on both panels of the card label to record Patient Number, the Visit Week, and 
Dispensing Date.  All investigational product labels comply with all applicable federal and local 
regulations.  

 
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5.1.5 
Storage of Clinical Supplies 
Clinical supplies must be stored in compliance with label requirements in a secure place and kept at room 
temperature; 25°C (77°F) with excursions permitted to 15°C to 30°C (59°F-86°F). 
5.1.6 
Study Medication Administration 
All patients will receive study medication according to the blister card numbers assigned by an interactive 
web response system (IWRS) randomization scheme.  Designated staff at each site will dispense study 
medication.  Study medication should be administered to the patient by the caregiver, family member, 
nursing home staff, or self-administered with supervision, except on the applicable clinic visit days when 
patients will be administered their dose of study medication at the clinic in the presence of site personnel, 
regardless of the time of day.  For Visits 2 (Day 8) and 2.1 (Day 15), the morning dose of study 
medication can be administered at home if the visit will occur within 2 hours of dosing; the time of dosing 
should be noted by the patient/caregiver.  Patients and caregivers will be instructed that the patient should 
take the study medication orally with water approximately every 12 hours ± 4 hours (morning and 
evening).  The time the patient takes each dose of medication should be recorded in the diary card.  
Patient’s missed doses will be noted in the electronic case report form (eCRF). 
All study medication will be supplied and administered in a double-blind manner throughout the entire 
duration of the study. 
5.2 
Accountability of Study Supplies 
5.2.1 
Receipt of Supplies 
The investigator is responsible for maintaining an inventory of each shipment of IP received and 
comparing it with the accompanying Drug Accountability Report/Material Shipping Form.  The 
investigator will verify the accuracy of the information on the form, sign and date it, and return the form 
to the sponsor or its representative.  All IP supplied is for use only in this study and should not be used for 
any other purpose.  All blister card material ID numbers will also be recorded and tracked at the site using 
the Drug Accountability Log. 
5.2.2 
Record of Dispensing 
Accurate recording of all IP dispensing for individual patients will be made in the appropriate section of 
the patient’s eCRF.  This eCRF will contain the following information: (i) patient number to whom the 
drug was dispensed; (ii) the date(s) and quantity of the drug dispensed to the patient; and (iii) the blister 
card material ID number assigned to the patient via IWRS.  
Additionally, the detachable panel of the two-panel label on each blister card will be removed and affixed 
to the study medication Dispensing Log page at the time of dispensing.  Space is provided on both panels 
of the blister card label to record patient number, the visit week and dispensing date.   

 
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5.2.3 
Unused Supplies 
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.  If any study medication is lost or damaged, it 
should be indicated on the form.  
5.3 
Methods of Assigning Patients to Treatment Groups 
5.3.1 
Randomization 
Upon entry into the study (after ICF is signed at screening), all patients will be assigned a 
patient 
number.  
 
.  This 
 number is the main identifier for patients. 
Stage 1 
Eligible patients will be randomized to receive AVP-786-28/4.9 capsules, AVP-786-18/4.9 capsules, or 
matching placebo capsules in a 
 ratio on Day 1 (Baseline, Stage 1) in a double-blind manner 
according to a randomization scheme devised by Avanir or its representative and managed within an 
IWRS.  The randomization will be stratified by NPI Agitation/Aggression domain score (≤ 6 vs. > 6), risk 
assessment for falls (normal/mild vs. moderate/severe), and concomitant use of antipsychotic medications 
(yes vs. no).  Blocked randomization is used to ensure treatment balance in each stratum.   
Stage 2 
Re-randomization will occur for patients who were assigned to placebo in Stage 1.  The patient number 
will not be re-assigned; it will remain the same in both stages of the study.   
• 
Patients who receive placebo in Stage 1 will be further stratified into two sub-groups (“responders” 
and “non-responders”) based on their treatment responses.  Patients will be considered “responders” 
if 
 
  Patients who do not meet 
 will be 
considered “non-responders”.  Patients within each placebo sub-group will be re-randomized in a 
 (active:active:placebo) ratio to receive either AVP-786-18/4.9, AVP-786-28/4.9 capsules, or 
matching placebo capsules.  
• 
Patients who receive placebo and who drop out early in Stage 1 will also be assigned a re-
randomization treatment in the same manner as the other placebo patients.  Their “responders” and 
“non-responders” status will be based on their treatment responses using measurements at their early 
termination visit.     
• 
Patients who receive AVP-786 in Stage 1 will not be re-randomized and will continue to receive the 
same dose of AVP-786 BID (either AVP-786-18/4.9 or AVP-786-28/4.9) for the entire 6-week 
duration of Stage 2. 

 
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5.3.2 
Blinding/Masking 
Blinding will be maintained by providing capsules of the 2 doses of AVP-786 and placebo that are 
identical in appearance.  The sponsor, patients, caregivers, investigators, or other study personnel will not 
be aware of a patient’s treatment assignment.  In the event that it becomes medically necessary to identify 
which treatment a patient has received, the blind can be broken.  In that event, the investigator is to 
contact Avanir’s medical monitor or representative to request the unmasking of a patient.  The IWRS 
manager is not required to be blinded and he or she will have access to the study medication list and the 
randomization code. 
5.4 
Patient Compliance 
Patients and caregivers will be instructed to bring any unused study medication and empty blister cards to 
the clinic on Days 8, 15, 22, 43, 64, and 85 (Visits 2 – 6).  For this study, compliance will be defined as 
when a patient takes at least 80% of their scheduled doses (compliance range 80-120%).  Caregivers will 
be provided with diary cards and will be instructed to record daily the number of capsules taken and the 
time of administration.  Diary cards will be reviewed for compliance and collected on Days 22, 43, 64, 
and 85 (Visits 3 – 6), or at the time of early study discontinuation.  Patients should bring their Diary Card 
on Day 8 (Visit 2) and Day 15 (Visit 2.1) for compliance review; the Diary Card will be returned to the 
patient and collected at the next visit.  
5.5 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
5.5.1 
 
 
 

 
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5.5.2 
Rescue Medication for the Symptoms of Agitation 
Patients will be allowed to receive oral lorazepam as rescue medication for the short-term treatment of 
symptoms of agitation if deemed necessary by the investigator.  Lorazepam will be administered in a dose 
up to 1.5 mg/day and not to exceed 3 days in a 7-day period.  Caregivers must record concomitant use of 
lorazepam in the diary and must be reminded of the potential increase in the risk of falling by 
benzodiazepines. 
5.5.3 
 
.  
 
 

 
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5.5.4 
Nondrug Therapies  
Information on any prior and concomitant nondrug therapies will be recorded. 
5.5.5 
Nonpharmacological Interventions for the Treatment of Agitation 
Information on any nonpharmacological interventions for the treatment of agitation that were used prior 
to enrollment or used concomitantly during the study will be recorded 
 

 
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6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Efficacy 
Samples of all the scales and questionnaires to be used during the study are attached as Appendices.  
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, NPI, mADCS-CGIC-Agitation, and CGIS-Agitation. 
6.1.1 
Cohen-Mansfield Agitation Inventory (CMAI) 
The CMAI will be used as the primary efficacy measure in this study.  The CMAI (Appendix 2) is used to 
assess the frequency of manifestations of agitated behaviors in elderly persons.  It consists of 29 agitated 
behaviors 
 
 
 
  
 
.  Each of 
the 29 items is rated on a 7-point scale of frequency (1 = never, 2 = less than once a week but still 
occurring, 3 = once or twice a week, 4 = several times a week, 5 = once or twice a day, 6 = several times a 
day, 7 = several times an hour).  The ratings are based on the 2 weeks preceding assessment of CMAI.  
The CMAI (long-form version, Appendix 2) will be assessed at Screening (Day -28 to Day -1), Baseline 
(Day 1), Day 8 (Visit 2), Day 15 (Visit 2.1), Day 22 (Visit 3), Day 43 (Visit 4), Day 64 (Visit 5), and 
Day 85 (Visit 6).  The CMAI must be administered by the same rater at each visit. 
6.1.2 
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.  The 
scripted NPI interview includes a compound screening question for each symptom domain, followed by a 
list of interrogatives about domain-specific behaviors that is administered when a positive response to a 
screening question is elicited.  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).  Frequency and severity rating scales have defined anchor points to 
enhance the reliability of caregiver responses.  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), 
Day 22 (Visit 3), Day 43 (Visit 4), Day 64 (Visit 5), and Day 85 (Visit 6).  The Agitation/Aggression 

 
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domain of the NPI will be administered to the patient’s caregiver at Screening (Day -28 to Day -1),Day 8 
(Visit 2) and Day 15 (Visit 2.1).  The NPI must be administered by the same rater at each visit. 
The NPI domains are generally evaluated for behaviors within the preceding 4 weeks but can be modified 
according to the needs of the study.  In this study, the recall period will be 2 weeks for all the visits 
The NPI nursing-home version (NPI-NH) will be used for patients from in-patient or assisted living 
facilities.  The questions in the NPI-NH were rephrased for professional caregivers who may not know 
the patients prior to the onset of illness; however, the overall instrument domains and scoring is identical 
to the NPI except for the caregiver distress section which is replaced with occupational disruptiveness in 
the NPI-NH version.    
The Agitation/Aggression domain in the NPI will be assessed as part of the total NPI as described above 
and the composite score obtained for this category will be recorded separately at Baseline (Day 1), 
Day 22 (Visit 3), Day 43 (Visit 4), Day 64 (Visit 5), and Day 85 (Visit 6). 
6.1.3 
Clinical Global Impression of Severity of Illness-Agitation (CGIS-
Agitation) 
The CGIS (Appendix 4) is an observer-rated scale that measures illness severity and is one of the most 
widely used brief assessment tools in psychiatry research.   
The Early Clinical Drug Evaluation Unit (ECDEU) version of the CGIS is the most widely used format of 
this validated tool, and asks that the clinician rate the patient relative to their past experience with other 
patients with the same diagnosis, with or without collateral information.  The CGIS has proved to be a 
robust measure of efficacy in many clinical drug trials26–30 and is easy and quick to administer, provided 
that the clinician knows the patient well.31  
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.32–34 
The CGIS is a 7-point (1-7) scale (1 = normal, not at all ill; 7 = among the most extremely ill patients) 
and assesses severity of agitation in this study.  The CGIS-Agitation will be assessed at Screening (Day -
28 to Day -1), Baseline (Day 1), Day 43 (Visit 4), and Day 85 (Visit 6).  The CGIS-Agitation must be 
administered by the same rater at each visit. 
6.1.4 
Alzheimer’s Disease Cooperative Study - Clinical Global 
Impression of Change Rating (ADCS-CGIC-Overall) 
The intent of the ADCS version of the CGIC (Appendix 5) (herein referred to as ADCS-CGIC-Overall), 
is to provide a means to reliably assess change from a baseline level of global function within the 
timeframe of a clinical trial.  Unlike a targeted symptom scale, the ADCS-CGIC-Overall takes into 
account a patient's overall function in the cognitive, behavioral and functional activity domains.  Relying 

 
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on information gathered through a semi-structured interview of the patient and caregiver, the 
ADCS-CGIC-Overall focuses on clinician’s observations of change in the patient's cognitive, functional, 
and behavioral performance since the beginning of a trial.  Once the baseline level of severity is 
established, the change score at the follow-up visits is based on information gathered from the patient and 
caregiver interviews.  The ADCS-CGIC-Overall is rated as: marked improvement, moderate 
improvement, minimal improvement, no change, minimal worsening, moderate worsening, or marked 
worsening.   
The baseline ADCS-CGIC-Overall evaluation will be conducted at the Baseline (Day 1) visit.  The 
ADCS-CGIC-Overall will be assessed at Day 43 (Visit 4) and Day 85 (Visit 6) for change in Overall 
Clinical Status.  At Day 43 (Visit 4), change from the Baseline visit (Day 1) will be assessed.  At Day 85 
(Visit 6), change from Day 43 (Visit 4) and change from the Baseline visit (Day 1) will be assessed.  
6.1.5 
Modified Alzheimer’s Disease Cooperative Study - Clinical Global 
Impression of Change Rating (mADCS-CGIC-Agitation) 
The standard ADCS-CGIC instrument was modified to better assess aspects relevant to studying agitation 
in AD (mADCS-CGIC-Agitation).  The mADCS-CGIC-Agitation (Appendix 6) contains questions 
related to agitation and an assessment of the Clinician’s Impression of Change focused specifically on 
agitation.  It was originally designed for the Citalopram study for Agitation in Alzheimer’s disease 
(CitAD)35,36 and utilizes a semi-structured interview of both patient and caregiver to determine a baseline 
level of severity for agitation.  Subsequent evaluations assess for change from baseline and also utilize the 
semi-structured agitation interview of both patient and caregiver.   
The baseline mADCS-CGIC-Agitation evaluation will be conducted at the Baseline (Day 1) visit.  The 
mADCS-CGIC-Agitation will be assessed at Day 43 (Visit 4) and Day 85 (Visit 6) for change in agitation 
syndrome.  At Day 43 (Visit 4), change from the Baseline visit (Day 1) will be assessed.  At Day 85 
(Visit 6), change from Day 43 (Visit 4) and change from the Baseline visit (Day 1) will be assessed.  The 
mADCS-CGIC-Agitation must be administered by the same rater at each visit. 
6.1.6 
Zarit Burden Interview (ZBI) 
The ZBI (Appendix 7) is a 22-item scale used to assess the impact of patient’s disabilities on the 
caregiver’s life.  It is designed to reflect the burden experienced by caregivers of dementia patients and 
can either be completed by the caregiver or administered as an interview.37  It is the most commonly used 
scale for measuring burden in caregivers’ of patients with dementia and also other illnesses.38  The ZBI 
has been shown to have high internal-reliability with an estimated Cronbach’s alpha at 0.88 and 0.91, and 
test-retest reliability at 0.71.  Validity has been estimated by correlating the total score with a single 
global rating of burden (r = 0.71).39  For each item of the scale, the caregiver has to indicate how often 
they felt that way (never, rarely, sometimes, quite frequently, or nearly always).  The score ranges from 
0 to 88 and is determined by adding the numbered responses of the individual items.  Higher scores 
indicate greater caregiver distress. 

 
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The ZBI will be assessed at Baseline (Day 1), Day 43 (Visit 4), and Day 85 (Visit 6). 
6.1.7 
Patient Global Impression of Change (PGIC) 
The PGIC (Appendix 8) is a 7-point (1-7) scale used to assess treatment response, and it is rated as: very 
much improved, much improved, minimally improved, no change, minimally worse, much worse, or very 
much worse.31 
The PGIC will be assessed and rated by the patient’s caregiver at Day 43 (Visit 4) and Day 85 (Visit 6) 
and will focus on the patient’s agitation.   
6.1.8 
Dementia Quality of Life (DEMQOL) 
The DEMQOL (Appendix 9) is a scale used to evaluate health related quality of life in patients with 
dementia and their caregivers.40  There are 2 versions of the DEMQOL, a 28-item version (rated by 
patient) and a 31-item version (DEMQOL-proxy, rated by caregiver).  Both the 28-item and 31-item 
version are recommended to be used for evaluating patients (and their caregivers) with mild to moderate 
dementia (MMSE ≥10).  For patients with severe dementia, only the DEMQOL-proxy (administered to 
caregiver) is used.    
The DEMQOL-proxy (and DEMQOL for patients with MMSE ≥10 at the Baseline visit) will be assessed 
at Baseline (Day 1), Day 43 (Visit 4), and Day 85 (Visit 6). 
6.1.9 
Alzheimer’s 
disease 
Assessment 
Scale-Cognitive 
Subscale 
(ADAS-cog) 
The ADAS (Appendix 10) was designed to evaluate the cognitive and non-cognitive behavioral 
dysfunction characteristics of patients with AD.41  The cognitive sub-scale (ADAS-cog) consists of 
11 subsets related to memory, praxis, and language.  The ADAS-cog takes about 30 to 45 minutes to 
complete.   
The ADAS-cog will be assessed at Baseline (Day 1), Day 43 (Visit 4), and Day 85 (Visit 6) for patients 
with an MMSE score of ≥ 10 at the Baseline visit. 
6.1.10 
Cornell Scale for Depression in Dementia (CSDD) 
The CSDD (Appendix 11) was specifically developed to assess signs and symptoms of major depression 
in patients with dementia.42  Because some of these patients may give unreliable reports, the CSDD uses a 
comprehensive interviewing approach that derives information from the patient and the caregiver.  
Information is elicited through two semi-structured interviews; an interview with a caregiver and an 
interview with the patient.  The interviews focus on depressive symptoms and signs occurring during the 
week preceding the assessment.  The CSDD takes approximately 20 minutes to administer.  
Each item is rated for severity on a scale of 0-2 (0 = absent, 1 = mild or intermittent, 2 = severe).  The 
item scores are added.  Scores above 10 indicate a probable major depression, scores above 18 indicate a 

 
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definite major depression, and scores below 6 as a rule are associated with absence of significant 
depressive symptoms. 
The CSDD will be assessed at Screening (Day -28 to Day -1), Day 43 (Visit 4), and Day 85 (Visit 6). 
6.1.11 
Resource Utilization in Dementia (RUD) 
The RUD (Appendix 12) is used to calculate healthcare costs associated with dementia.43  It evaluates 
dementia patients’ utilization of formal and informal healthcare resources, including hospitalizations and 
doctor visits, living assistance, and time spent by non-professional caregivers.  Within the context of 
clinical trials, the RUD is often used to determine the cost effectiveness of new pharmaceutical 
treatments.44   
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 (e.g., 
hours of caregiver time, visits to doctors, nights in accommodation) by the corresponding unit price 
vector. 
The RUD will be assessed at Baseline (Day 1), Day 43 (Visit 4), and Day 85 (Visit 6). 
6.1.12 
General Medical Health Rating (GMHR)  
The GMHR (Appendix 13) is a global clinical rating for medical health, designed to quantify in a single 
number (1 to 4) the severity of general co-morbidity in a patient with dementia.45  A rating of 1 = poor, 2 
= fair, 3 = good and 4 = excellent to very good.    
The GMHR will be assessed at Screening (Day -28 to Day -1) and Day 85 (Visit 6). 
6.2 
Pharmacokinetics (PK) 
At Day 43 (Visit 4) and Day 85 (Visit 6), patients will have a blood sample collected between 0 to 3 
hours after the morning dose of study medication for analysis of plasma levels of d6-DM, d6-DM 
metabolites and Q.  The time when the patient was administered the dose of study medication and the 
time of the blood draw will be recorded on the eCRF.  Plasma samples will be separated by centrifugation 
and then frozen at -20° C until assayed at the analytical unit.  

 
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6.3 
Safety 
6.3.1 
Adverse Events 
6.3.1.1 
Definitions 
An adverse event (AE) is any untoward medical occurrence or unintended change (including physical, 
psychological, or behavioral) from the time ICF is signed, including inter-current illness, which occurs 
during the course of a clinical trial after treatment has started, whether considered related to treatment or 
not.  An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  Changes associated with normal growth and 
development that do not vary in frequency or magnitude from that ordinarily anticipated clinically are not 
AEs (e.g., onset of menstruation occurring at a physiologically appropriate time). 
Clinical AEs should be described by diagnosis and not by symptoms when possible (e.g., cold, seasonal 
allergies, instead of “runny nose”). 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than specified in 
the protocol and higher than known therapeutic doses.  It must be reported irrespective of outcome even if 
toxic effects were not observed. 
AEs will be graded on a 3-point scale and reported in detail as indicated on the eCRF: 
 
Mild:  
easily tolerated, causing minimal discomfort and not interfering with  
normal everyday activities 
 
Moderate:  
sufficiently discomforting to interfere with normal everyday activities 
 
Severe:  
incapacitating and/or preventing normal everyday activities 
The relationship of each AE to study medication should be determined by the investigator using the 
following explanations: 
 
Not related:  
the event is clearly related to other factors such as the patient’s clinical state, 
therapeutic interventions, or concomitant medications administered to the patient 
 
Unlikely related:  
the event is most likely produced by other factors such as the patient’s clinical 
state, therapeutic interventions, or concomitant medications administered to the 
patient; and does not follow a known response pattern to the study medication 
 
Possibly related:  
the event follows a reasonable temporal sequence from the time of drug 
administration; and/or follows a known response pattern to the study medication; 
but could have been produced by other factors such as the patient’s clinical state, 
therapeutic interventions, or concomitant medications administered to the patient 
 
Related:  
 the event follows a reasonable temporal sequence from the time of drug 
administration; and follows a known response pattern to the study medication; 

 
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and cannot be reasonably explained by other factors such as the patient’s clinical 
state, therapeutic interventions, or concomitant medications administered to the 
patient 
6.3.1.2 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any AE occurring at any dose that results in any of the following 
outcomes: 
1. Death 
2. Life-threatening experience (one that places the patient, in the view of the initial reporter, at 
immediate risk of death from the AE as it occurred, i.e., it does not include an AE that, had it 
occurred in a more severe form, might have caused death) 
3. Persistent or significant disability/incapacity (disability is a substantial disruption of a person’s 
ability to conduct normal life functions) 
4. In-patient hospitalization or prolongation of hospitalization 
5. Congenital anomaly/birth defect 
Important medical events that may not result in death, or be life-threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the 
patient or require medical or surgical intervention to prevent one of the outcomes listed in the definition. 
The terms “cancer” and “overdose” are not considered to be SAEs, but if a patient experiences cancer or 
overdose, they are still reportable as AEs. 
Pregnancy is not considered to be an AE or an SAE, unless a complication occurs that meets the 
requirements for an AE or SAE, but must be reported on a pregnancy report form.  Women who are 
pregnant or likely to become pregnant are excluded from this study.  In the event a patient becomes 
pregnant during the study, study medication must be discontinued, a pregnancy report form must be 
completed to capture potential drug exposure during pregnancy, and the pregnancy must be reported 
within 24 hours of notice.  Any pregnant patient must be followed until the outcome of her pregnancy is 
known (i.e., normal delivery, abnormal delivery, spontaneous/voluntary/therapeutic abortion).  The 
pregnancy (i.e., the mother and the fetus) must be followed up through delivery with regard to outcome.  
A pregnancy report form must also be completed in the event that a female partner of a male patient 
becomes pregnant within 30 days after his last dose of study medication or study completion, whichever 
is greater.  
The term ‘severe’ is a measure of intensity; thus a severe AE is not necessarily serious.  For example, 
nausea of several hours duration may be rated as severe, but may not be clinically serious. 

 
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6.3.1.3 
Reporting 
Caregivers will be queried regarding AEs at each clinic visit after the screening visit (Baseline [Day 1], 
Days 8, 15, 22, 43, 64, and 85 [Visits 2-6]) and at safety follow-up phone calls at Days 29 and 71.  The 
investigator will assess and record all reported AEs.  Any AE newly reported after receiving the last dose 
of study medication will be followed up until 30 days.  
A death occurring during the study, or which comes to the attention of the investigator within 30 days 
after stopping the treatment whether considered treatment-related or not, must be reported to the sponsor. 
For all SAEs, including an abnormal laboratory test value, the investigator should consult with Avanir’s 
MM or designated representative as needed and report any SAE by fax/email form no later than 24 hours 
after becoming aware of the event.  Subsequently, the SAE must be assessed for the following details: 
seriousness of event, start date, stop date, intensity, frequency, relationship to test drug, action taken 
regarding test drug, treatment required, and outcome to date.  These details must be recorded on the 
clinical study AE form that is provided.  This form should be transmitted by fax and the details given by 
telephone to the contact numbers below. 
SAE reporting by FAX or e-mail correspondence  
FAX:  
 
E-mail: 
 
SAE hotline (24-hour/7 days a week) 
Phone: 
 
Such preliminary reports will be followed by detailed descriptions later, which may include copies of 
hospital case reports, autopsy reports, and other related documents when requested. 
The Institutional Review Board/Ethics Committee (IRB/EC) will be notified of such an event in writing 
as soon as is practical in compliance with federal and local regulations. 
6.3.1.4 
Procedures to be followed in the Event of Abnormal Test Values 
Any patients with clinically significant abnormal laboratory test results may be required by the MM to 
have a repeat test 1 week later or earlier, if medically indicated.  Clinically significant laboratory 
abnormalities may be a basis for exclusion from study entry. 
6.3.2 
Physical and Neurological Examinations 
Physical and neurological examinations will be performed at Screening (Day -28 to Day -1), Day 43 
(Visit 4), and Day 85 (Visit 6).  The physical examination will include assessments of head, eyes, ears, 
nose, throat, lymph nodes, skin, extremities, respiratory, gastrointestinal, musculoskeletal, cardiovascular, 
and nervous systems.  The neurological examination will include assessments of mental status, cranial 
nerves, motor system, reflexes, coordination, gait and station, and sensory system.  The physical and 
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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. 
6.3.3 
Vital Signs 
Orthostatic blood pressure (BP) and heart rate (HR) measurements will be performed at all clinic visits.  
Supine BP and HR will be measured after a patient has rested for at least 5 minutes in the supine position.  
Each measurement will be taken twice in the same position and recorded.  After the measurement of 
supine BP and HR, the patient will stand still for up to 3 minutes and a single measurement of standing 
BP and HR will be recorded within these 3 minutes of standing.  
Respiratory rate (breaths/minute) and body temperature (ºF) will be assessed at all clinic visits.  Weight 
will be recorded at Baseline (Day 1) and Day 85 (Visit 6).  
6.3.4 
Clinical Laboratory Tests 
The following clinical laboratory assessments are to be performed at Screening (Day -28 to Day -1), 
Day 22 (Visit 3), Day 43 (Visit 4), Day 64 (Visit 5), and Day 85 (Visit 6): 
• 
Blood chemistry (calcium, magnesium, phosphorus, glucose, sodium, potassium, chloride, 
carbon dioxide, blood urea nitrogen [BUN], serum creatinine, uric acid, albumin, total bilirubin, 
alkaline phosphatase, lactate dehydrogenase [LDH], aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase [AST/SGOT], alanine aminotransferase/serum glutamic pyruvic 
transaminase [ALT/SGPT], creatine kinase [CK], gamma-glutamyl transferase [GGT], 
triglycerides, total protein, and total cholesterol) 
• 
Hematology (red blood cell [RBC] count, hemoglobin, hematocrit, white blood cell [WBC] 
count, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, platelet count, and 
morphology) 
• 
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 6 only 
Any patients with clinically significant abnormal laboratory test results may be required by the MM to 
have a repeat test 1 week later or earlier, if medically indicated.  Clinically significant laboratory 
abnormalities may be a basis for exclusion from study entry. 

 
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6.3.5 
Pregnancy Tests 
Urine pregnancy tests are to be performed for females of childbearing potential at Screening (Day -28 to 
Day -1), Baseline (Day 1), Day 43 (Visit 4), and Day 85 (Visit 6). 
All female patients of childbearing potential should be instructed to use appropriate birth control methods 
for up to 4 weeks following the last dose of study medication.  
6.3.6 
Electrocardiograms 
A resting 12-lead ECG will be performed at all clinic visits except on Day 8 (Visit 2).  At Screening, ECG 
will be performed in triplicate.  At Baseline (Day 1) and Day 43 (Visit 4), two ECGs will be performed; 
one prior to study medication dosing and one 2-3 hours after dosing.  ECG equipment will be provided by 
the central reader.  ECG data will be recorded at the study center and will include general findings, heart 
rate (beats/minute) QRS complex and PR and QTc intervals (milliseconds).  Results will be provided by 
the central reader to the investigators within 24 hours.  ECG data will be transferred automatically from 
the central reader into the eCRF monthly.  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 the study MM and, if necessary be repeated within a 1-week period. 
6.3.7 
Sheehan Suicidality Tracking Scale (S-STS)  
The S-STS (Appendix 14) is a prospective scale that assesses treatment-emergent suicidal thoughts and 
behaviors.46  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 Sheehan-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), Day 8 (Visit 2), Day 15 
(Visit 2.1), Day 22 (Visit 3), Day 43 (Visit 4), Day 64 (Visit 5), and Day 85 (Visit 6).  Any change in the 
S-STS score indicating the presence of suicidality should be evaluated by the investigator and reported to 
the MM. 
6.3.8 
Mini-Mental State Examination (MMSE) 
The MMSE (Appendix 15) 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.47  It requires only 5 to 10 minutes for a trained rater to 
administer it. 

 
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The MMSE will be assessed at Screening (Day -28 to Day -1), Baseline (Day 1), Day 43 (Visit 4), and 
Day 85 (Visit 6). 
6.3.9 
Timed Up and Go (TUG) Test 
The TUG test (Appendix 16) 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.48,49  
The TUG test will be performed at Screening (Day -28 to Day -1), Day 43 (Visit 4), and Day 85 (Visit 6).  
6.3.10 
Epworth Sleepiness Scale (ESS) 
The ESS (Appendix 17) 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.50  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), Day 43 (Visit 4), and Day 85 (Visit 6).  
6.4 
Schedule of Evaluations and Procedures 
A schedule of evaluations and procedures for both Stage 1 and Stage 2 is provided in Table 1. 
6.4.1 
Description of Study Procedures 
At each visit throughout the study, site staff will be required to enter information into the IWRS regarding 
patient data and pre-defined study assessment results.  Further instructions will be provided in the IWRS 
Site Manual. 
6.4.1.1 
Screening Visit (Days -28 to -1, + 3-day window) 
The 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 the MM.  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. 

 
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2. Medical history, including patient demographics, any prior and concomitant medications (including 
OTC, vitamins, and supplements), nondrug therapies, and any nonpharmacological interventions for 
the treatment of agitation will be reviewed and recorded. 
3. Review inclusion/exclusion criteria (eligibility form). 
4. Vital signs will be measured and recorded.  
5. Physical and neurological examination will be performed. 
6. Risk assessment for falls will be performed (worksheet and TUG test). 
7. A resting 12-lead ECG will be performed in triplicate. 
8. A blood and urine specimen will be collected for safety laboratory assessments.  
9. A urine pregnancy test will be performed for females of childbearing potential only. 
10. The following assessments will be completed: 
• 
MMSE; a score between 6 and 26 (inclusive) is required for study entry 
• 
CMAI 
• 
NPI Agitation/Aggression domain 
• 
CGIS-Agitation; a score of ≥ 4 is required for study entry 
• 
S-STS  
• 
CSDD; a score of <10 is required for study entry 
• 
GMHR 
Following screening procedures for assessment of inclusion and exclusion criteria, the site will complete 
a protocol eligibility form and submit to the MM for approval.  Patients deemed eligible by the PI and the 
MM will be randomized into 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. 
6.4.1.2 
Baseline Visit (Day 1) 
The Baseline visit (Day 1) should occur in the morning.  The following procedures will be performed.  
Before Dosing: 
1. Inclusion/exclusion criteria will be reviewed. 

 
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2. Caregivers will be queried regarding AEs, concomitant medication use (including OTC, vitamins, 
and supplements) nondrug therapies, and concomitant nonpharmacological interventions for the 
treatment of agitation. 
3. Vital signs and weight will be measured and recorded.  
4. A resting 12-lead ECG will be performed (twice this visit - pre and 2-3 hours post dose). 
5. A blood specimen will be collected 
. 
6. A urine pregnancy test will be performed for females of childbearing potential only. 
7. The following assessments will be completed: 
• 
MMSE 
• 
CMAI  
• 
NPI 
• 
CGIS-Agitation  
• 
Baseline mADCS-CGIC-Agitation 
• 
ADAS-cog (only for patients with an MMSE score of ≥ 10 at baseline) 
• 
DEMQOL-proxy (and DEMQOL for patients with an MMSE score of ≥ 10 at baseline) 
• 
S-STS  
• 
ZBI 
• 
RUD 
• 
Baseline ADCS-CGIC-Overall 
• 
ESS 
Patients will be randomized once it is determined that they satisfy all of the inclusion and none of the 
exclusion criteria (on the basis of the screening and baseline assessments described above) and will be 
assigned with a study medication kit number via IWRS. 
Study Medication Dosing: 
The first dose of study medication will be administered from the AM strip of blister card at the clinic 
regardless of the time of day.   

 
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After Dosing: 
1. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication. 
2. The caregiver will be queried regarding AEs. 
3. Patient Diary Card and sufficient study medication for a 3-week treatment period will be 
dispensed. 
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule of 
study medication from the top row [AM] of blister card in the morning and 1 capsule of study medication 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 4 hours) for 
7 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card.  They will also be 
instructed to consult with the study site prior to taking any non-study medications.  These requirements 
will be reviewed in person.  Caregivers will also be instructed to bring to the clinic any unused study 
medication and patient’s Diary Card at each study visit.  For the next scheduled visit (Visit 2), caregivers 
will be advised to administer the morning dose of study medication to the patient within 2 hours of the 
clinic appointment and note the time of dosing. 
Caregivers will be queried at the end of each visit to be certain they understand what is required of them. 
6.4.1.3 
Visit 2 (Day 8 + 3-day window) 
Visit 2 (Day 8) should occur in the morning within 2 hours of taking the AM dose.  The morning dose of 
study medication can be administered at home if the visit will occur within 2 hours of dosing; the time of 
dosing should be noted by the patient/caregiver.   
The following procedures will be performed: 
1. 
The caregiver will be queried regarding AEs, concomitant medication use (including OTC, 
vitamins, and supplements), nondrug therapies, and concomitant nonpharmacological interventions 
for the treatment of agitation. 
2. 
Vital signs will be measured and recorded. 
3. 
The following assessments will be completed: 
• 
CMAI 
• 
NPI Agitation/Aggression domain 
• 
S-STS 

 
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4. 
Unused study medication will be accounted for compliance and the blister card returned to the 
patient. 
5. 
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 medication twice-daily (1 capsule of 
study medication from the top row [AM] of blister card in the morning and 1 capsule of study medication 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 4 hours) for 
7 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card.  They will also be 
instructed to consult with the study site prior to taking any non-study medications.  These requirements 
will be reviewed in person.  Caregivers will also be instructed to bring to the clinic any unused study 
medication and patient’s Diary Card at each study visit.  For the next scheduled visit (Visit 2.1), 
caregivers will be advised to administer the morning dose of study medication to the patient within 2 
hours of the clinic appointment and note the time of dosing. 
 
Caregivers will be queried at the end of each visit to be certain they understand what is required of them. 
6.4.1.4 
Visit 2.1 (Day 15 ± 3-day window) 
Visit 2.1 (Day 15) should occur in the morning within 2 hours of taking the AM dose.  The morning dose 
of study medication can be administered at home if the visit will occur within 2 hours of dosing; the time 
of dosing should be noted by the patient/caregiver.   
The following procedures will be performed: 
1. 
A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication. 
2. 
The caregiver will be queried regarding AEs, concomitant medication use (including OTC, 
vitamins, and supplements), nondrug therapies, and concomitant nonpharmacological interventions 
for the treatment of agitation. 
3. 
Vital signs will be measured and recorded. 
4. 
The following assessments will be completed: 
• 
CMAI 
• 
NPI Agitation/Aggression domain 
• 
S-STS 

 
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5. 
Unused study medication will be accounted for compliance and the blister card returned to the 
patient. 
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 medication twice-daily (1 capsule of 
study medication from the top row [AM] of blister card in the morning and 1 capsule of study medication 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 4 hours) for 
7 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card.  They will also be 
instructed to consult with the study site prior to taking any non-study medications.  These requirements 
will be reviewed in person.  Caregivers will also be instructed to bring to the clinic any unused study 
medication and patient’s Diary Card at each study visit.  Caregivers will be queried at the end of each 
visit to be certain they understand what is required of them. 
6.4.1.5 
Visit 3 (Day 22 ± 3-day window) 
Visit 3 (Day 22) should occur in the morning.  The following procedures will be performed.  
Before Dosing: 
1. The caregiver will be queried regarding AEs, concomitant medication use (including OTC, vitamins, 
and supplements), nondrug therapies, and concomitant nonpharmacological interventions for the 
treatment of agitation. 
2. Vital signs will be measured and recorded. 
3. Returned, unused study medication will be accounted for compliance. 
4. Patient’s Diary Card will be collected and reviewed for compliance. 
5. The following assessments will be completed: 
• 
CMAI 
• 
NPI  
• 
S-STS  
Study Medication Dosing: 
Study medication will be administered from the AM strip of the newly dispensed blister card at the clinic 
regardless of the time of day.   

 
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After Dosing: 
1. A blood and urine specimen will be collected within 3 hours for safety laboratory assessments. 
2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication. 
3. Patient Diary Card and sufficient study medication for a 3-week treatment period will be dispensed. 
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule of 
study medication from the top row [AM] of blister card in the morning and 1 capsule of study medication 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 4 hours) for 
21 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card.  They will also be 
instructed to consult with the study site prior to taking any non-study medications.  These requirements 
will be reviewed in person.  Caregivers will also be instructed to bring to the clinic any unused study 
medication at each study visit.  Caregivers will be queried at the end of each visit to be certain that they 
understand what is required of them. 
6.4.1.6 
Visit 4 (Day 43 ± 3-day window) 
Visit 4 (Day 43) should occur in the morning.  The following procedures will be performed  
Before Dosing (End of Stage 1): 
1. The caregiver will be queried regarding AEs, concomitant medication use (including OTC, vitamins, 
and supplements), nondrug therapies, and concomitant nonpharmacological interventions for the 
treatment of agitation. 
2. Vital signs will be measured and recorded. 
3. Physical and neurological examination will be performed. 
4. A resting 12-lead ECG will be performed (twice this visit - pre and 2-3 hours post dose) 
5. Patient’s Diary Card will be collected and reviewed for compliance. 
6. Returned, unused study medication will be accounted for compliance. 
7. The following assessments will be completed: 
• 
CMAI 
• 
NPI 
• 
CGIS-Agitation 

 
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• 
mADCS-CGIC-Agitation 
• 
ADCS-CGIC-Overall 
Beginning of Stage 2 
Patients will be re-randomized after the procedures above have been completed.  A new study medication 
kit number will be assigned via IWRS.  The patient number will remain the same. 
Study Medication Dosing: 
Study medication will be administered from the AM strip of the newly dispensed blister card at the clinic 
regardless of the time of day. 
After Dosing: 
1. A blood specimen will be collected within 3 hours after the morning dose of study medication for 
PK analysis and for safety laboratory assessments.   
2. A urine sample will be collected for urinalysis. 
3. Urinary pregnancy test will be performed in women of childbearing potential. 
4. The following assessments will be completed: 
• 
MMSE 
• 
ADAS-cog (only for patients with an MMSE score of ≥ 10 at baseline) 
• 
CSDD 
• 
DEMQOL-proxy (and DEMQOL for patients with an MMSE score of ≥ 10 at baseline) 
• 
S-STS 
• 
TUG 
• 
ZBI 
• 
RUD 
• 
PGIC 
• 
ESS 
5. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication.  
6. A new patient’s Diary Card will be dispensed. 
7. Sufficient study medication for a 3-week treatment period will be dispensed. 

 
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Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule of 
study medication from the top row [AM] of blister card in the morning and 1 capsule of study medication 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 4 hours) for 
21 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card.  They will also be 
instructed to consult with the study site prior to taking any non-study medications.  These requirements 
will be reviewed in person.  Caregivers will also be instructed to bring to the clinic any unused study 
medication at each study visit.  Caregivers will be queried at the end of each visit to be certain that they 
understand what is required of them. 
6.4.1.7 
Visit 5 (Day 64 ± 3-day window) 
Visit 5 (Day 64) should occur in the morning.  The following procedures will be performed.  
Before Dosing: 
1. The caregiver will be queried regarding AEs, concomitant medication use (including OTC, vitamins, 
and supplements), nondrug therapies, and concomitant nonpharmacological interventions for the 
treatment of agitation. 
2. Vital signs will be measured and recorded. 
3. Returned, unused study medication will be accounted for compliance. 
4. Patient’s Diary Card will be collected and reviewed for compliance. 
5. The following assessments will be completed: 
• 
CMAI 
• 
NPI  
• 
S-STS  
Study Medication Dosing: 
Study medication will be administered from the AM strip of the newly dispensed blister card at the clinic 
regardless of the time of day.   

 
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After Dosing: 
1. A blood and urine specimen will be collected within 3 hours for safety laboratory assessments. 
2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication. 
3. Patient Diary Card and sufficient study medication will be dispensed for a 3-week treatment period. 
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule of 
study medication from the top row [AM] of blister card in the morning and 1 capsule of study medication 
from the bottom row [PM] of the blister card in the evening, approximately every 12 hours ± 4 hours) for 
21 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the patient’s Diary Card.  They will also be 
instructed to consult with the study site prior to taking any non-study medications.  These requirements 
will be reviewed in person.  Caregivers will also be instructed to bring to the clinic any unused study 
medication at each study visit.  Caregivers will be queried at the end of each visit to be certain that they 
understand what is required of them. 
6.4.1.8 
Visit 6 (Day 85 ± 3-day window) / Early Termination 
Visit 6 (Day 85) should occur in the morning.  Patients who withdraw prior to study completion are 
required to complete study procedures as listed in Visit 6 within 48 hours of the last dose of study 
medication.  There is no specific time frame for the 12-lead ECG, and sample blood/urine specimen 
collection (safety labs and PK samples) for early termination patients. 
The last dose of study medication will be administered to the patient at the clinic regardless of the time of 
day, from the blister card brought in by the patient. 
The following procedures will be performed after dosing:  
1. The caregiver will be queried regarding AEs, concomitant medication use (including OTC, vitamins, 
and supplements), nondrug therapies, and concomitant nonpharmacological interventions for the 
treatment of agitation. 
2. Returned, unused study medication will be accounted for compliance. 
3. Patient’s Diary Card will be collected and reviewed. 
4. Vital signs and weight will be measured and recorded. 
5. Physical and neurological examination will be performed. 
6. The following assessments will be completed: 

 
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• 
MMSE 
• 
CMAI 
• 
NPI 
• 
CGIS-Agitation  
• 
mADCS-CGIC-Agitation 
• 
ADAS-cog (only for patients with an MMSE score of ≥ 10 at baseline) 
• 
CSDD 
• 
DEMQOL-proxy (and DEMQOL for patients with an MMSE score of ≥ 10 at baseline) 
• 
S-STS 
• 
TUG 
• 
GMHR 
• 
ZBI 
• 
RUD 
• 
ADCS-CGIC-Overall 
• 
PGIC 
• 
ESS 
7. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication. 
8. A blood specimen will be collected within 3 hours after the morning dose of study medication for 
PK analysis and for safety laboratory assessments.   
9. A urine sample will be collected for urinalysis. 
10. Urinary pregnancy test will be performed in women of childbearing potential. 
Any previously reported and not yet resolved AE, and any newly reported AE at the time of this visit will 
be followed-up for up to 30 days after the last dose of study medication.  

 
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6.4.1.9 
Follow-up Phone Call (Days 29 and 71, + 3-day window) 
Patient’s caregiver will receive a safety follow-up phone call on Days 29 and 71.  Caregiver will be 
queried on adverse events, concomitant medication use, nondrug therapies, and nonpharmacological 
interventions for agitation, since the last visit.  Patients who terminate early from the study or who do not 
roll over to the extension study (Study 15-AVP-786-303) will receive a safety follow-up phone call 30 
days after the last dose of study medication.  

 
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7 
DATA MANAGEMENT 
7.1 
Data Collection 
The sponsor or designated representative (e.g., CRO) will perform the data management activities in 
accordance with the data management plan (DMP).  The DMP will outline the systems and procedures to 
be used in the study. 
Clinical study data will be reported (captured) by study site personnel on eCRFs.  An eCRF must be 
completed for every patient enrolled in the study.  The eCRF data will be entered by trained study-site 
personnel and then reviewed for completeness and accuracy and electronically signed by the investigator 
or authorized designee.  All study-site personnel must use a password-protected user account to enter, 
review, or correct study data.  Electronic signature procedures shall comply with the CFR Title 21 
Part 11.  Passwords will be strictly confidential. 
All eCRF data will be exported from the electronic data capture (EDC) system and transferred to the 
sponsor or representative.  The sponsor or representative will also receive electronic transfers of non-
eCRF data such as laboratory data from the central laboratory, ECG data from the central ECG reader, as 
well as other data from third-party vendors as appropriate.  The electronic data format of all transfers will 
be agreed upon with the sponsor or representative and documented in the DMP or vendor data transfer 
requirements document as appropriate. 
The clinical monitoring staff will perform source data verification (SDV) of the data recorded in the EDC 
system with source documents at the clinical study sites according to the data management plan and 
clinical monitoring plan.  The data will be subjected to consistency and validation checks within the EDC 
system with supplemental data reviews performed outside of the EDC system.   
Medical history and adverse events will be coded using a current version of Medical Dictionary for 
Regulatory Activities (MedDRA), and concomitant medications using a current version of the WHO Drug 
Dictionary.  The sponsor or representative will perform a medical safety review of the coding. 
Completed eCRF images with a date- and time-stamped electronic audit trail indicating the user, the data 
entered, and any reason for change (if applicable) will be archived at the investigator’s site and at the 
sponsor’s site. 
 

 
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8 
STATISTICAL METHODS 
8.1 
Analysis Populations 
Three analysis populations will be used, modified intent-to-treat (mITT), intent-to-treat (ITT), and safety. 
• 
mITT:  The mITT population includes all patients randomized in the study who had at least one 
post-baseline efficacy assessment.  The mITT population will be used for all analyses of efficacy.  
Patients will be included in the treatment group to which they were randomized regardless of 
treatment received.  
• 
ITT:  The ITT population includes all randomized patients in the study.  The ITT population will 
be used for exploratory efficacy analyses. 
• 
Safety:  The safety population includes all patients who received study treatment.  The safety 
population will be used for all analyses of safety.  Patients will be included in the treatment group 
based on the actual treatment received. 
8.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group for the ITT and mITT 
populations using descriptive statistics.  
8.3 
Efficacy Analysis 
The efficacy measures are assessed in each of the two stages of the trial.  For the primary efficacy 
analysis, as well as for all other efficacy analyses, the SPCD method will be used to combine data from 
Stage 1 and 2.  Data from Stage 1 placebo non-responders who are re-randomized into Stage 2 will be 
used to estimate Stage 2 treatment effect.  
8.3.1 
Study Endpoints 
Primary efficacy endpoint: 
The primary efficacy endpoint is the change from Baseline to Week 6 (Day 43, Stage 1) and from Week 6 
to Week 12 (Day 85, Stage 2) in the composite CMAI scores. 
 
Secondary efficacy endpoints: 
The secondary efficacy endpoints are the change from Baseline to Week 6 (Day 43, Stage 1) and from 
Week 6 to Week 12 (Day 85, Stage 2) in the following measures:   
• mADCS-CGIC-Agitation   
• NPI – Agitation/Aggression domain score and Caregiver Distress score 

 
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• NPI - Aberrant Motor Behavior domain 
• ZBI 
• NPI - Irritability/Lability domain 
• Total NPI 
• CGIS-Agitation  
• ADCS-CGIC-Overall  
• PGIC  
• DEMQOL  
• CSDD  
• ADAS-cog   
• RUD 
• GMHR (change from Baseline to Week 12 (Day 85) 
8.3.2 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from Baseline to Week 6 (Day 43, Stage 1) and from Week 6 
to Week 12 (Day 85, Stage 2) in the composite CMAI scores.  The primary efficacy analysis will be 
based on SPCD method using a weighted test statistics combining treatment effects from Stage 1 and 2.3  
Data from Stage 1 placebo non-responders who are re-randomized into Stage 2 will be used to estimate 
Stage 2 treatment effect. 
For the primary efficacy endpoint, the null hypothesis is that there is no treatment effect in Stage 1 and 
Stage 2 and it will be tested against the alternative that there is a treatment effect in at least one of the 2 
stages.  The treatment effect in each stage will be estimated by using a likelihood-based linear mixed 
effects model repeated measures (MMRM) on observed data.  The model will include fixed effects for 
treatment, visit, treatment-by-visit interaction, baseline-by-visit interaction and baseline covariates which 
include baseline value and other randomization stratification factors.  An unstructured covariance model 
will be used.  Analyses with missing values imputed by last observation carried forward (LOCF) and 
Multiple Imputation (MI) may be performed as sensitivity analyses. 
The 2 primary comparisons are AVP-786-28/4.9 vs. placebo and AVP-786-18/4.9 vs. placebo.  An 
appropriate multiple comparison procedure will be used to control the overall type I error at 2-sided α = 
0.05.   
8.3.3 
Secondary Efficacy Analyses 
Secondary efficacy endpoints include change from Baseline to Week 6 (Day 43, Stage 1) and from 
Week 6 to Week 12 (Day 85, Stage 2) for the following efficacy measures: mADCS-CGIC-Agitation, 

 
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NPI Agitation/Aggression domain score and Caregiver Distress score, NPI-Aberrant Motor Behavior 
domain score, ZBI, NPI-Irritability/Lability domain score, PGIC, DEMQOL, CSDD, RUD, total NPI, 
CGIS-Agitation, ADCS-CGIC-Overall, ADAS-cog; and change from Baseline to Week 12 for GMHR.   
Treatment comparison tests using similar SPCD method as the primary efficacy analysis will be 
performed.  A proper multiple comparison procedure, e.g, gate keeping procedure, will be used to control 
overall type I error at 2-sided α = 0.05 for treatment comparisons (high dose vs. placebo, low dose vs. 
placebo) and the secondary endpoints tested.  The testing procedure will be pre-specified in the statistical 
analysis plan (SAP) before un-blinding the study.  
 
 
  Detailed analyses will 
be described in the SAP. 
8.4 
PK/PD Analysis 
Plasma concentrations of d6-DM, its metabolites, and Q will be measured and results will be summarized 
descriptively overall 
.  Plasma 
concentration results will be used to assess the PK properties of d6-DM and its metabolites.  Additional 
PK/PD correlations may also be performed.  Additional details will be described in the SAP. 
8.5 
  
 
    
8.6 
Safety Analysis 
Safety will be assessed by the following measurements:  AEs, physical and neurological examination, 
vital signs, urine pregnancy test, clinical laboratory assessments, resting 12-lead ECG, S-STS, MMSE, 
TUG test, and ESS.  All safety measures will be summarized by Stage 1, Stage 2, and the 2 stages 
combined. 
Safety analyses will consist of data summaries for biological parameters and AEs.  Safety analyses will be 
tabulated by treatment.   
8.6.1 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The percentages 
of patients experiencing 1 or more AEs will be summarized by treatment, system organ class (SOC), 
deaths, non-fatal SAEs, AEs, AEs resulting in study discontinuation, and treatment-emergent AEs 
(TEAE).  TEAEs are those AEs that occur after the first dose of study medication up until 30 days after 
last dose.   

 
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8.6.2 
Vital Signs and ECGs  
Summary statistics of absolute values and percentage change from baseline for BP (diastolic and 
systolic), heart rate, respiratory rate, and ECG parameters will be provided.  All values outside a pre-
defined normal range will be highlighted in the individual patient data listings. 
8.6.3 
Clinical Laboratory Values 
Laboratory parameters will be summarized via descriptive statistics and via shifts in results in respect to 
normal ranges between Screening and end of treatment as increased, decreased, or no change.  
8.6.4 
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.  
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. 
8.6.5 
Interim Analysis 
Interim analysis may be performed and will be pre-specified in the SAP. 
8.7 
Sample Size Calculations  
Power calculations were performed assuming a bivariate normal distribution for the primary efficacy 
endpoint with AVP-786-28/4.9 (high dose) versus placebo.  
 
 
 
 
  
 
 

 
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  To control the 
overall type I error rate at 
 level, the null hypothesis about the low dose AVP-786-18/4.9 will be 
tested only if the null hypothesis about the high dose is rejected. 

 
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9 
ADMINISTRATIVE PROCEDURES 
9.1 
Institutional Review Board/Ethics Committee Approval 
Institutional Review Boards/Ethics Committees (IRBs/ECs) must meet the guidelines set out by the FDA 
and conform to local laws and customs where appropriate.  Written IRB/EC approval for the protocol and 
the signed ICF must be obtained and transmitted to Avanir Pharmaceuticals or representative before the 
study can be initiated.  The IRB/EC must be informed of and approve all protocol amendments.  The 
investigator will ensure that this study is conducted in full conformance with local laws and according to 
National and State/Provincial laws (Appendix 18, Investigator Responsibilities).  The complete text of the 
World Medical Association Declaration of Helsinki is given in Appendix 19. 
9.2 
Informed Consent Form 
The ICF will follow the principles outlined in the current version of the Declaration of Helsinki.  For each 
patient found to be eligible for the study, informed consent will be obtained from the patient (if the patient 
is capable in the judgment of the investigator to provide informed consent) or the authorized 
representative.  For patients that are not capable of providing informed consent, but are capable of 
providing assent, the patient will be asked to provide assent.  If the patient is not capable of providing 
assent, the investigator will document the reasons why and maintain that documentation with the other 
informed consent documents.  The patient’s caregiver will also be asked to provide informed consent as 
they will be providing data on themselves and the patient, as well as, being responsible for ensuring 
compliance from the patient between study visits. 
The patients and/or patient’s authorized representative and the caregiver will be properly informed of the 
purpose of the study.  The patients and/or patient’s authorized representative and the caregiver will be 
alerted to any anticipated AE that may be encountered with the study medication.  A signed ICF will be 
obtained from all patients and/or patient’s authorized representative and the caregiver prior to patient 
entry into this study.  Patients and/or patient’s authorized representative and the caregiver will be 
provided with a copy of their signed ICF. 
9.3 
Patient’s Diary Card 
The patient’s Diary Card will be reviewed by clinical study personnel at all study treatment visits for 
confirmation of medication dosage and any rescue medication received.  The study personnel are 
responsible for (i) ensuring that patients and/or caregivers are properly collecting data and recording it 
into the diaries; and (ii) transcribing the diary recordings into the eCRF.  The diary will be collected at all 
study visits after baseline except Visit 2 (Day 8) and Visit 2.1 (Day 15), wherein the diary will be 
reviewed and returned to the patient.  The originals of all diaries will be maintained at the site as source 
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9.4 
Electronic Case Report Forms 
For each patient enrolled who has given informed consent, an eCRF must be completed and electronically 
signed by the investigator to certify that the data within each eCRF are complete and correct.  This also 
applies to those patients who fail to complete the study.  If a patient is withdrawn from the study because 
of a treatment-limiting AE, thorough efforts should be made to document the outcome.  
Any site personnel delegated responsibility for data entry, query resolution, or eCRF approval must 
complete training prior to accessing the eCRF.  The electronic data capture (EDC) vendor will provide 
user-specific access to the live (production) eCRF once training completion has been confirmed and the 
account has been approved by the sponsor.  Changes to the data once it has been initially saved will be 
tracked via audit trail and will require a reason for the change.  The audit trail will also include who made 
the change and a date/time stamp. 
The eCRFs will be reviewed by the study monitor at the study site.  Errors detected by subsequent in-
house data review may necessitate clarification or correction of errors.  All changes will be documented 
and approved by the investigator. 
All investigators will be provided with copies of the eCRFs for their site on a CD-ROM at the end of the 
study. 
9.5 
Quality Assurance 
9.5.1 
Documentation 
For each process, evaluation, or test that generates study data but is not described in the protocol or eCRF, 
a written description of the data generation procedures shall be retained in the quality assurance section of 
the study files.  In the case of routine clinical diagnostic procedures, only a copy of the relevant 
certification document is required. 
9.5.2 
Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the investigator.  
This will include telephone calls and on-site visits.  The study will be routinely monitored to ensure 
compliance with the study protocol and the overall quality of data collected.  During the on-site visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol.  As part of the data audit, source 
documents will be made available for review by the study monitor.  The study monitor may periodically 
request review of the investigator study file to assure the completeness of documentation in all respects of 
clinical study conduct. 
The study monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative and the caregiver for study procedures and for the release of medical 
records to the sponsor, FDA, other regulatory authorities, and the IRB/EC.  The study monitor will also 
verify that assent was obtained for patients not capable of providing informed consent or that 

 
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documentation is provided by the investigator explaining why the patient was unable to provide assent.  
The investigator or appointed delegate will receive the study monitor during these on-site visits and will 
cooperate in providing the documents for inspection and respond to inquiries.  In addition, the 
investigator will permit inspection of the study files by authorized representatives of the regulatory 
agencies. 
On completion of the study, the study monitor will arrange for a final review of the study files after which 
the files should be secured for the appropriate time period. 
9.6 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Avanir, the investigator agrees to keep 
records, including the identity of all participating patients (sufficient information to link records, e.g., 
CRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant correspondence 
(e.g., letters, meeting minutes, telephone calls reports).  The records should be retained by the investigator 
according to ICH, local regulations, or as specified in the Clinical Trial Agreement, whichever is longer. 
If the investigator is unable for any reason to continue to retain study records for the required period (e.g., 
retirement, relocation), Avanir should be prospectively notified.  The study records must be transferred to 
a designee acceptable by Avanir, such as another investigator, another institution, or to Avanir.  The 
investigator must obtain Avanir’s written permission before disposing of any records, even if retention 
requirements have been met. 
9.7 
Source Data 
The documents that will form the source data for the clinical study (e.g., patient charts, laboratory reports) 
must be defined and documented in the in-house study master file prior to the start of the study.  Data on 
the eCRFs which will be checked against source data during monitoring visits must also be defined and 
documented in the in-house study master file including the percentage of each of the source data to be 
verified and the percentage of patients’ eCRFs to be monitored. 
9.8 
Data Handling 
Data collected on the eCRFs will be entered into EDC system by trained site staff.  Any queries arising 
from data entry will be checked with the investigator and changes approved.  
9.9 
Laboratory Procedures 
Each individual site laboratory will collect hematology and chemistry blood samples and urine samples at 
Screening (Day -28 to Day -1), and Visits 3-6 (Day 22, Day 43, Day 64, and Day 85) for safety analysis.  
Instructions for specimen evaluation and transport to a central laboratory will be provided at the time of 
study initiation.  Blood samples will also be taken 
 at Baseline (Day 1) and for 

 
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PK analysis on Visits 4 and 6 (Day 43 and Day 85).  Instructions for shipping the laboratory samples for 
evaluation by central facilities will be provided. 
9.10 
Guidelines for Good Clinical Practice 
Standards for GCP must be adhered to for all study-based procedures. 
9.11 
Conditions for Amending the Protocol 
Protocol modification to ongoing studies which could potentially adversely affect the safety of patients or 
which alter the scope of the investigation, the scientific quality of the study, the experimental design, 
dosages, duration of therapy, assessment variables, the number of patients treated, or patient selection 
criteria must be made only after appropriate consultation between an appropriate representative of Avanir 
and the investigator. 
Protocol modifications must be prepared by a representative of Avanir or the investigator, and reviewed 
and approved by Avanir.   
All protocol modifications must be reviewed and approved by the appropriate IRB/EC in accordance with 
local requirements, before the revised edition can be implemented.  Modifications which eliminate an 
apparent immediate hazard to patients do not require pre-approval by the IRB/EC. 
9.12 
Conditions for Terminating the Study 
Both Avanir and the principal investigator reserve the right to terminate the study at the site at any time.  
Should this be necessary, the procedures to effect study termination will be arranged after review and 
consultation by both parties.  In terminating the study, Avanir and the investigator will assure that 
adequate consideration is given to the protection of the patient’s interests. 
9.13 
Confidentiality of Study Documents and Patient Records 
The investigator must assure that the patient’s anonymity will be maintained.  On eCRFs or other 
documents submitted to Avanir, patients should not be identified by their names but by an identification 
code. 
The investigator should keep a separate log of patient’s codes, names, and addresses.  Documents not for 
submission to Avanir, for example, patients’ signed ICFs, should be maintained by the investigator in 
strict confidence. 
9.14 
Reports 
At the completion of the study, the investigator shall provide the sponsor with an adequate report shortly 
after completion of the investigator's participation in the study as described in the Code of Federal 
Regulations (CFR) Title 21, Part 312.64. 

 
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9.15 
Publications 
It is anticipated that a report of this study will be published in the scientific literature by the sponsor.  The 
investigator will not seek to arrange for publication of any of the information or results from the study in 
any scientific journal, or other publication or by way of lecture without Avanir’s prior review and written 
consent.  
9.16 
Audits/Inspections 
The investigator should understand that source documents for this study should be made available to 
appropriately qualified personnel or designee(s) from Avanir or to health authority inspectors after 
appropriate notification.  The verification of the eCRF data may be by direct inspection of source 
documents (where permitted by law) or through an interview exchange. 
The inspector from the regulatory authority will be especially interested in the following items: 
• 
Visits from the sponsor’s representatives 
• 
IRB/EC approval(s) 
• 
Study medication accountability 
• 
Study protocol and amendments 
• 
ICFs of the patient (if capable of providing ICF, according to the investigator) or patient’s 
authorized representatives and caregivers 
• 
Assent of the patients (if capable of providing assent, according to the investigator) 
• 
Medical records supportive of eCRF data 
• 
Reports to the IRB/EC and the sponsor 
• 
Record retention 
The sponsor will be available to help investigators prepare for an inspection. 

 
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REFERENCES 

 
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APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 18: 
Investigator Responsibilities 
 
 
 

 
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15-AVP-786_ADCS-CGIC_Follow-Up_V6_English_v1.0_FINAL_22JUL2015.DOC

15-AVP-786_ADCS-CGIC_Follow-Up_V6_English_v1.0_FINAL_22JUL2015.DOC

 
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15-AVP-786_mADCS-CGIC_Follow-up_v6_ English_v2.0_FINAL_28JUL2015.DOC          

15-AVP-786_mADCS-CGIC_Follow-up_v6_ English_v2.0_FINAL_28JUL2015.DOC          

 
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Appendix 18: Investigator Responsibilities 
 

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

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

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

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

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4.3.4  Although a subject is not obliged to give his/her reason(s) for withdrawing
prematurely from a trial, the investigator should make a reasonable effort to
ascertain the reason(s), while fully respecting the subject's rights.
4.4
Communication with IRB/IEC
4.4.1  Before initiating a trial, the investigator/institution should have written and
dated approval/favorable opinion from the IRB/IEC for the trial protocol, written
informed consent form, consent form updates, subject recruitment procedures
(e.g., advertisements), and any other written information to be provided to
subjects. 
4.4.2  As part of the investigator's/institution’s written application to the IRB/IEC,
the investigator/institution should provide the IRB/IEC with a current copy of the
Investigator's Brochure.  If the Investigator's Brochure is updated during the trial,
the investigator/institution should supply a copy of the updated Investigator’s
Brochure to the IRB/IEC.
4.4.3  During the trial the investigator/institution should provide to the IRB/IEC all
documents subject to its review.  
4.5
Compliance with Protocol
4.5.1  The investigator/institution should conduct the trial in compliance with the
protocol agreed to by the sponsor and, if required, by the regulatory authority(ies),
and which was given approval/favorable opinion by the IRB/IEC.  The
investigator/institution and the sponsor should sign the protocol, or an alternative
contract, to confirm their agreement.
4.5.2  The investigator should not implement any deviation from, or changes of,
the protocol without agreement by the sponsor and prior review and documented
approval/favorable opinion from the IRB/IEC of an amendment, except where
necessary to eliminate an immediate hazard(s) to trial subjects, or when the
change(s)  involves only logistical or administrative aspects of the trial (e.g.,
change of monitor(s), change of telephone number(s)).
4.5.3  The investigator, or person designated by the investigator, should document
and explain any deviation from the approved protocol.
4.5.4  The investigator may implement a deviation from, or a change in, the
protocol to eliminate an immediate hazard(s) to trial subjects without prior
IRB/IEC approval/favorable opinion.  As soon as possible, the implemented

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 deviation or change, the reasons for it, and, if appropriate, the proposed protocol
amendment(s) should be submitted:
(a)  To the IRB/IEC for review and approval/favorable opinion;
(b)  To the sponsor for agreement and, if required; 
(c)  To the regulatory authority(ies).
4.6
Investigational Product(s)
4.6.1  Responsibility for investigational product(s) accountability at the trial site(s)
rests with the investigator/institution.
4.6.2  Where allowed/required, the investigator/institution may/should assign some
or all of the investigator's/institution’s duties for investigational product(s)
accountability at the trial site(s) to an appropriate pharmacist or another
appropriate individual who is under the supervision of the investigator/institution.
4.6.3  The investigator/institution and/or a pharmacist or other appropriate
individual, who is designated by the investigator/institution, should maintain
records of the product's delivery to the trial site, the inventory at the site, the use
by each subject, and the return to the sponsor or alternative disposition of unused
product(s).  These records should include dates, quantities, batch/serial numbers,
expiration dates (if applicable), and the unique code numbers assigned to the
investigational product(s) and trial subjects. Investigators should maintain records
that document adequately that the subjects were provided the doses specified by
the protocol and reconcile all investigational product(s) received from the sponsor.
4.6.4  The investigational product(s) should be stored as specified by the sponsor
(see sections 5.13.2 and 5.14.3) and in accordance with applicable regulatory
requirement(s).
4.6.5  The investigator should ensure that the investigational product(s) are used
only in accordance with the approved protocol.
4.6.6  The investigator, or a person designated by the investigator/institution,
should explain the correct use of the investigational product(s) to each subject and
should check, at intervals appropriate for the trial, that each subject is following
the instructions properly.
4.7
Randomization Procedures and Unblinding
The investigator should follow the trial's randomization procedures, if any, and should
ensure that the code is broken only in accordance with the protocol.  If the trial is blinded,

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

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

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

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

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

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

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

 
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