A 52-Week Open-Label Extension Study of Pimavanserin for the Treatment of Agitation and Aggression in Subjects With Alzheimer's Disease
Phase: PHASE2
Conditions: Agitation and Aggression in Alzheimer's Disease
Sponsor: ACADIA Pharmaceuticals Inc.

Official Title: 52-week open-label extension study of pimavanserin for the treatment 
of agitation and aggression in subjects with Alzheimer’s disease 
NCT Number: NCT03118947 
Date of IRB Approval: 30 Nov 2017 

 
 
ACADIA Pharmaceuticals Inc. 
 
Clinical Study Protocol 
Amendment 3 
A 52-Week Open-Label Extension Study of Pimavanserin for 
the Treatment of Agitation and Aggression in Subjects With 
Alzheimer’s Disease 
Protocol No. ACP-103-033 
EudraCT Number: 2016-001128-78 
 
Original Protocol Date: 17 May 2016 
Amendment 01 Protocol Date: 20 September 2016 
Amendment 2 Protocol Date: 18 July 2017 
Amendment 3 Protocol Date: 30 November 2017 
 
 
 
Confidentiality Statement 
 
This protocol is the confidential information of ACADIA Pharmaceuticals Inc. and is 
intended solely for the guidance of the clinical investigation. This protocol may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of ACADIA Pharmaceuticals Inc. 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.
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SPONSOR CONTACTS 
ACADIA Medical Contact: 
 
 
 
 
 
 
 
 
 
ACADIA Clinical Contact: 
 
 
 
 
 
  
 
 
Study: ACP-103-033
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Final Version: 1.0
Date: 30 November 2017
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PROTOCOL SYNOPSIS 
Title 
A 52-Week Open-Label Extension Study of Pimavanserin for the 
Treatment of Agitation and Aggression in Subjects With Alzheimer’s 
Disease 
Protocol Number 
ACP-103-033 
Name of Drug 
Pimavanserin 
Indication 
Agitation and Aggression in Alzheimer’s Disease (AD) 
Phase of 
Development 
2 
Sponsor 
ACADIA Pharmaceuticals Inc. 
 
Sponsor Contact 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
  
Test Product, Dose, 
and Mode of 
Administration: 
Pimavanserin 34 mg (provided as 2×17 mg tablets), or pimavanserin 
20 mg (provided as 2×10 mg tablets) will be administered orally once 
daily (QD). 17 mg of the active moiety is dosed as 20 mg of the salt 
pimavanserin tartrate; 10 mg of the active moiety is dosed as 11.8 mg 
of the salt pimavanserin tartrate. 
Number of Study 
Sites 
Approximately 70 study sites will participate in this study. 
Objectives 
The purpose of this study is to evaluate the safety and tolerability of 
pimavanserin treatment with up to 52 weeks of exposure (~64 weeks 
total for subjects who received pimavanserin in Study ACP-103-032), 
in subjects with probable AD. 
Primary Objective: 
To evaluate the safety and tolerability of pimavanserin after 52 weeks 
of treatment in subjects with probable AD who have symptoms of 
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agitation and aggression. 
Exploratory Objectives: 
To evaluate the persistence of the effects of pimavanserin treatment 
on: 
 Agitation and aggression  
 Caregiver burden 
 The clinician’s global assessment of treatment benefit 
 Other neuropsychiatric symptoms 
 Cognition 
 Functional status 
 Sleep and daytime wakefulness  
Methodology 
This protocol describes an open-label extension study to determine the 
safety and tolerability of pimavanserin for the treatment of agitation 
and aggression in subjects with probable AD. This study will be 
conducted as a 52-week, open-label, flexible-dose extension of Study 
ACP-103-032. 
Subjects must have completed ACP-103-032 and must meet eligibility 
criteria to qualify for enrollment. 
Study ACP-103-033 subjects must be consented prior to the final 
procedures being performed for Study ACP-103-032 at Week 12. 
Procedures from the Week 12 visit of Study ACP-103-032 will be 
carried over to the ACP-103-033 study to be included as baseline 
information and this visit will be considered the Baseline Visit 
(Visit 1) of the ACP-103-033 study. 
Treatment Period (Baseline through Week 52) 
All subjects will receive once daily (QD) doses of pimavanserin 
(active study drug) over 52 weeks of treatment, starting with 20 mg 
pimavanserin. After the first 2 weeks, the daily dose can be adjusted to 
either 34 mg or 20 mg pimavanserin, based on the Investigator’s 
assessment of clinical response. Dose adjustments can be made at 
scheduled or unscheduled visits. 
During the Treatment Period, clinic visits will be conducted at 
Baseline and Weeks 2, 4, 8, 12, 20, 28, 36, 44, and 52, or upon early 
termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the 
Baseline visit. The subject and his/her study partner/caregiver will be 
provided instructions to take the first dose of study drug on the 
following day. It is recommended that the subject take the study drug 
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at approximately the same time each day. 
All concomitant antidepressants, cholinesterase inhibitors, memantine, 
and other permitted medications should remain at a stable dose 
throughout the study, if possible. 
A follow-up safety assessment will be conducted by telephone call at 
approximately 30 days after the last dose of study medication. 
Number of Subjects 
Planned  
Up to approximately 111 male and female subjects with probable AD 
who have symptoms of agitation and aggression, who have completed 
Study ACP-103-032, and meet eligibility criteria for ACP 103-033 
will enroll in this study. 
Duration of 
Treatment  
The total duration of participation for individual subjects will be up to 
approximately 56 weeks. Each subject will participate in a 52-week 
treatment period followed by an approximately 30-day follow-up 
period. The end of the clinical trial will be when the last subject 
completes the last scheduled assessment (i.e., 30-day follow-up). 
Subject Assignment Not applicable, as this is an open-label extension study. 
Study Population 
Subjects who fulfill all of the inclusion criteria and none of the 
exclusion criteria are eligible to participate in the study. 
Inclusion Criteria: 
1. Can understand the nature of the trial and protocol requirements 
and provide signed informed consent and can understand and sign 
other forms necessary for participation in the trial (e.g., the Health 
Insurance Portability and Accountability Act [HIPAA] 
authorization form in the United States). The following 
requirements for consent must be met: 
o from the subject, if the subject is deemed competent to 
provide informed consent 
o from an appropriate person according to national and local 
regulations (e.g., the subject’s legally authorized 
representative [LAR] with the subject’s assent), if the subject 
is deemed not competent to provide informed consent 
2. Lives at home or in an assisted living or care facility (but has the 
capacity to visit the clinic as an outpatient) 
3. Has a designated study partner/caregiver (e.g., relative, housemate, 
close personal friend, or professional caregiver) who is in contact 
with the subject at least 3 times a week on 3 separate days. The 
study partner/caregiver should: 
o be willing and able to accompany the subject to all clinic visits, 
o be capable of routinely monitoring and reporting study drug 
use, 
o be regarded by the Investigator as sufficiently informed to 
report accurately on the subject’s behavioral and functional 
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status. 
4. The subject’s study partner/caregiver provides written agreement 
that they understand the study, including the role of the study 
partner/caregiver and will participate in the study  
5. Both subject and study partner/caregiver are fluent in and able to 
read the local language in which study assessments are 
administered at the clinical site 
6. Both subject and study partner/caregiver are willing and able to 
participate in all scheduled evaluations and complete all required 
tests 
7. Must complete the Week 12 visit in Study ACP-103-032 while 
continuing to take his/her assigned dose of blinded study drug 
8. If female, must be of non-childbearing potential (defined as either 
surgically sterilized or at least 1 year postmenopausal) or must 
agree to use a clinically acceptable method of contraception (e.g., 
oral, intrauterine device [IUD; diaphragm], injectable, transdermal 
or implantable contraception) or abstinence during the study, and 
1 month following completion of the study. 
Females of childbearing potential must have a negative urine 
human chorionic gonadotropin (hCG) pregnancy test at Baseline  
Exclusion Criteria: 
1. Is participating in another clinical trial (other than Study 
ACP-103-032) of any investigational drug, device, or intervention 
2. The Investigator determines that enrollment in the study would be 
detrimental to a subject’s well-being 
3. The Investigator becomes aware of an impending and unexpected 
change in the subject’s living situation (e.g., change in caregiver, 
change in facility, moving from home to facility, moving from one 
family member or caregiver’s home to another) that s/he judges 
may cause a major disruption in the subject’s behavior 
4. Subject or study partner/caregiver has an uncorrected medical 
condition (e.g., hearing, vision impairments) that would impair the 
ability to perform the study assessments. 
5. Subject is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study 
6. Subject was significantly non-compliant in Study ACP-103-032 
7. Subject has had a QRS interval <120 ms and whose Fridericia’s 
corrected QT interval (QTcF) is >460 ms at baseline OR subject 
has had a QRS interval ≥120 ms and QTcF is >480 ms at Baseline 
8. Has clinically significant laboratory abnormalities that in the 
judgment of the Investigator would jeopardize the safe 
participation of the subject in the study 
9. Subject has become bedridden or has any significant medical 
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condition that is unstable and that would either: 
o place the subject at undue risk from study drug or undergoing 
study procedures; or 
o interfere with the interpretation of safety or efficacy 
evaluations performed during the course of the study 
10. Subject is receiving skilled nursing care for any medical condition 
other than dementia (skilled nursing care includes procedures that 
can only be administered by a registered nurse or doctor, such as 
[but not limited to] intravenous administration of medication, 
procedures related to insertion or care of suprapubic catheters, and 
nasopharyngeal/tracheostomy aspiration)  
11. Has a Global Clinician Assessment of Suicidality (GCAS) score of 
3 or 4 based on Investigator’s assessment of behavior since the last 
assessment 
Primary Endpoint  
Primary Endpoint: 
 Treatment emergent adverse events (TEAEs) 
Safety and 
Tolerability 
Assessments and 
Endpoints 
Safety Endpoints: 
 Serious AEs (SAEs) and withdrawals due to AEs  
 Global Clinician Assessment of Suicidality (GCAS) 
 Clinically important changes from Baseline in vital sign 
measurements, weight, clinical laboratory assessments, physical 
examinations, and electrocardiograms (ECGs) 
Assessments and 
Exploratory 
Endpoints 
Exploratory Endpoints: 
 Change from Baseline in Cohen-Mansfield Agitation Inventory 
(CMAI) total score  
 Change from Baseline in Zarit Burden Interview (ZBI) total 
score  
 Modified Alzheimer’s Disease Cooperative Study-Clinical 
Global Impression of Change (mADCS-CGIC) agitation score  
 Change from Baseline in Neuropsychiatric Inventory-Clinician 
Rating Scale (NPI-C) combined agitation and aggression 
domain scores 
 Change from Baseline in NPI-C total score  
 Change from Baseline in NPI-C individual domain scores 
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 Change from Baseline in Mini-Mental State Examination 
(MMSE) score 
 Change from Baseline in Karolinska Sleepiness Scale (KSS) 
score 
 Change from Baseline in CMAI subscale scores  
 Change from Baseline in Alzheimer’s Disease Cooperative 
Study-Activities of Daily Living (ADCS-ADL) score 
Sample Size 
Calculations 
Sample size for this study is not based on statistical power, but will 
depend on the number of subjects who complete Study ACP-103-032 
and who transition into this open-label extension study. 
Statistical Methods The purpose of this study is to collect safety data from subjects after 
exposure to pimavanserin for a total duration of up to 52 weeks. 
Exploratory objectives include assessment of efficacy outcome 
measures over time. No formal statistical testing will be performed for 
any of the safety or efficacy endpoints. 
All safety and efficacy measures will be summarized for the overall 
safety population. Summaries by treatment group according to the 
original treatment in Study ACP-103-032 (placebo, pimavanserin 
20 mg, and pimavanserin 34 mg) will also be provided.  
For each continuous measure in safety and efficacy analyses, change 
from Baseline results will be presented in three ways: 
1. Using the Baseline from Study ACP-103-033 and reporting the 
changes across Study ACP-103-033 timepoints; 
2. Using the Baseline from Study ACP-103-032 and reporting the 
changes across the timepoints of both the double-blind Study 
ACP-103-032 and the open-label Study ACP-103-033; 
3. Based on the Baseline before the first dose of pimavanserin in 
either Study ACP-103-032 or ACP-103-033; changes will be 
reported across the timepoints using the Baseline from the 
double-blind Study ACP-103-032 for subjects receiving 
pimavanserin in the double-blind study (up to 64 weeks), and 
using the Baseline from Study ACP-103-033 for subjects 
receiving placebo in the double-blind study (up to 52 weeks). 
Descriptive Statistics 
Continuous measurement results will be reported using the number of 
subjects with data values, mean, standard error of the mean, median, 
standard deviation, minimum, and maximum. For each categorical 
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outcome, the frequency and percentage of subjects in each category 
will be reported. 
Safety Analyses 
Safety results will be summarized by treatment group using 
descriptive statistics. Adverse events will be classified into standard 
terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events leading to discontinuation, AEs related to 
study drug, AEs by maximum severity, SAEs, fatal AEs, and SAEs 
related to study drug will be reported. 
Descriptive statistics for ECGs, vital signs and body weight, and 
clinical laboratory parameters, including changes from baseline, will 
be tabulated by treatment group and timepoint. Additionally, 
categorical analyses will be conducted on the incidence of subjects 
with prolonged QTc intervals and changes in QTc intervals in 
accordance with International Council for Harmonisation (ICH) 
guidelines. 
Subgroup Analyses 
Selected subgroup analyses will be specified in the statistical analysis 
plan (SAP). 
Date 
30 November 2017 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE .............................................................................................. 2 
SPONSOR CONTACTS ........................................................................................................... 3 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
TABLE OF CONTENTS......................................................................................................... 11 
LIST OF TABLES ................................................................................................................... 14 
LIST OF APPENDICES .......................................................................................................... 14 
ABBREVIATIONS AND ACRONYMS ................................................................................ 15 
1 BACKGROUND INFORMATION .................................................................................. 17 
1.1 
Investigational Drug ................................................................................................. 19 
1.2 
Previous Clinical Experience ................................................................................... 19 
1.3 
Study Rationale ........................................................................................................ 20 
2 OBJECTIVES .................................................................................................................... 21 
2.1 
Primary Objective and Endpoints ............................................................................ 21 
2.1.1 
Primary Objective ....................................................................................... 21 
2.1.2 
Primary Endpoint ........................................................................................ 21 
2.1.3 
Safety Endpoints ......................................................................................... 21 
2.2 
Exploratory Objectives and Endpoints ..................................................................... 21 
2.2.1 
Exploratory Objectives ............................................................................... 21 
2.2.2 
Exploratory Endpoints ................................................................................ 22 
3 STUDY DESIGN .............................................................................................................. 22 
3.1 
Overall Study Design ............................................................................................... 22 
3.1.1 
Study Duration ............................................................................................ 23 
3.2 
Dose Rationale ......................................................................................................... 24 
3.3 
Number of Subjects .................................................................................................. 24 
3.4 
Study Procedures ...................................................................................................... 24 
3.4.1 
Site Initiation Procedures ............................................................................ 24 
3.4.2 
Schedule of Events and Assessments.......................................................... 25 
3.4.3 
Visit 1 (Baseline) ........................................................................................ 25 
3.4.4 
Visit 2 (Week 2) .......................................................................................... 26 
3.4.5 
Visit 3 (Week 4) .......................................................................................... 26 
3.4.6 
Visit 4 (Week 8) .......................................................................................... 27 
3.4.7 
Visits 5, 6, 7, 8, and 9 (Weeks 12, 20, 28, 36, and 44) ............................... 27 
3.4.8 
Visit 10 (Week 52 [End-of-Study/Early Termination]) .............................. 28 
3.4.9 
Unscheduled Visits ..................................................................................... 28 
3.4.10 Visit 11 (30-day Safety Follow-up, Week 56, Telephone) ......................... 29 
4 SELECTION OF SUBJECTS AND CRITERIA FOR WITHDRAWAL ........................ 29 
4.1 
Selection of Subjects ................................................................................................ 29 
4.1.1 
Inclusion Criteria ........................................................................................ 29 
4.1.2 
Exclusion Criteria ....................................................................................... 30 
4.2 
Subject Withdrawal .................................................................................................. 31 
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4.2.1 
Criteria for Subject Withdrawal .................................................................. 32 
5 TREATMENTS ADMINISTERED .................................................................................. 33 
5.1 
Identity of Investigational Product ........................................................................... 33 
5.2 
Administration of Study Drug .................................................................................. 33 
5.3 
Overdose .................................................................................................................. 33 
5.4 
Dosage Adjustments ................................................................................................. 33 
5.5 
Method of Assigning Subjects to Treatment Groups ............................................... 33 
5.6 
Concomitant Medications ........................................................................................ 34 
5.6.1 
Permitted Concomitant Medications ........................................................... 34 
5.6.2 
Prohibited and Restricted Medications ....................................................... 34 
5.6.3 
Rescue Medications .................................................................................... 34 
5.7 
Blinding .................................................................................................................... 35 
5.8 
Investigational Drug Handling ................................................................................. 35 
5.8.1 
Test Article .................................................................................................. 35 
5.8.2 
Investigational Drug Packaging .................................................................. 35 
5.8.3 
Receipt of Investigational Drug Supplies ................................................... 35 
5.8.4 
Storage of Investigational Drug .................................................................. 35 
5.8.5 
Investigational Drug Dosing ....................................................................... 36 
5.8.5.1 Treatment Period .......................................................................... 36 
5.8.6 
Record of Dispensing .................................................................................. 36 
5.8.7 
Accountability ............................................................................................. 36 
6 EFFICACY AND SAFETY ASSESSMENTS ................................................................. 37 
6.1 
Efficacy Assessments ............................................................................................... 37 
6.1.1 
Cohen-Mansfield Agitation Inventory ........................................................ 37 
6.1.2 
Zarit Burden Interview ................................................................................ 37 
6.1.3 
Neuropsychiatric Inventory – Clinician Rating Scale................................. 38 
6.1.4 
Mini–Mental State Examination ................................................................. 38 
6.1.5 
Modified Alzheimer’s Disease Cooperative Study - Clinical Global 
Impression-Change ..................................................................................... 38 
6.1.6 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
Inventory ..................................................................................................... 39 
6.1.7 
Karolinska Sleepiness Scale ....................................................................... 39 
6.2 
Safety Assessments .................................................................................................. 39 
6.2.1 
Medical and Medication History ................................................................ 39 
6.2.2 
Alzheimer’s Disease History ...................................................................... 40 
6.2.3 
Physical Examinations ................................................................................ 40 
6.2.4 
Vital Signs ................................................................................................... 40 
6.2.5 
Weight ......................................................................................................... 40 
6.2.6 
Electrocardiograms ..................................................................................... 40 
6.2.7 
Safety Laboratory Evaluations .................................................................... 40 
6.2.8 
Clinically Significant Abnormalities .......................................................... 42 
6.2.9 
Suicidal Ideation and Behavior ................................................................... 42 
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7 ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING .................. 42 
7.1 
Adverse Events ......................................................................................................... 42 
7.2 
Definition of Adverse Events ................................................................................... 43 
7.3 
Serious Adverse Events and Unexpected Adverse Events....................................... 46 
7.3.1 
Elective Procedures and Surgeries .............................................................. 47 
7.4 
Other Reportable Information .................................................................................. 48 
7.5 
Suspected Unexpected Serious Adverse Reaction ................................................... 48 
7.5.1 
Serious Adverse Event Reporting ............................................................... 48 
7.6 
Routine Safety Monitoring ....................................................................................... 49 
7.7 
Pregnancy ................................................................................................................. 49 
7.8 
Emergency Treatment .............................................................................................. 49 
8 DATA RECORDING, RETENTION, AND MONITORING .......................................... 50 
8.1 
Case Report Forms and Data Verification ............................................................... 50 
8.2 
Source Documentation ............................................................................................. 50 
8.3 
Availability and Retention of Records ..................................................................... 50 
8.4 
Quality Control and Quality Assurance ................................................................... 51 
8.5 
Subject Confidentiality ............................................................................................. 51 
9 STATISTICAL PLAN ....................................................................................................... 52 
9.1 
General Statistical Methods ..................................................................................... 52 
9.2 
Determination of Sample Size ................................................................................. 53 
9.3 
Handling of Dropouts and Missing Data ................................................................. 53 
9.4 
Subgroup Analyses ................................................................................................... 53 
9.5 
Study Subjects .......................................................................................................... 53 
9.5.1 
Analysis Sets ............................................................................................... 53 
9.5.2 
Subject Accountability and Subject Disposition ......................................... 53 
9.5.3 
Demographic and Baseline Characteristics ................................................ 53 
9.6 
Efficacy Analyses ..................................................................................................... 53 
9.7 
Safety Analyses ........................................................................................................ 54 
9.7.1 
Exposure to Study Drug .............................................................................. 54 
9.7.2 
Adverse Events ........................................................................................... 54 
9.7.3 
Clinical Laboratory Values ......................................................................... 54 
9.7.4 
Vital Signs and Body Weight ..................................................................... 54 
9.7.5 
Electrocardiogram ....................................................................................... 54 
9.7.6 
Physical Examinations ................................................................................ 55 
9.7.7 
Suicidal Ideation and Behavior ................................................................... 55 
10 REGULATORY COMPLIANCE ..................................................................................... 55 
10.1 Institutional Review Board ...................................................................................... 55 
10.2 Ethical Conduct of the Study ................................................................................... 55 
10.3 Subject Information and Informed Consent ............................................................. 55 
10.4 Finance, Insurance, and Indemnity .......................................................................... 56 
10.5 Protocol Amendments .............................................................................................. 56 
10.6 Protocol Exceptions and Deviations ........................................................................ 57 
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10.7 Termination of the Study ......................................................................................... 57
10.8 Publication ................................................................................................................ 57
11 DECLARATION OF INVESTIGATOR........................................................................... 58
12 REFERENCES .................................................................................................................. 59
13 APPENDICES ................................................................................................................... 63
LIST OF TABLES
Table 6–1 
Safety Laboratory Evaluations......................................................................... 42
LIST OF APPENDICES
Appendix A 
Schedule of Events and Assessments .............................................................. 64
Appendix B 
Prohibited and Restricted Concomitant Medications ...................................... 66
Appendix C 
List of Prohibited CYP3A4 Inducers and Inhibitors ....................................... 69
Appendix D 
Cohen-Mansfield Agitation Inventory (CMAI)  SAMPLE ........................... 70 
Appendix E 
Zarit Burden Interview (ZBI)  SAMPLE ...................................................... 74 
Appendix F 
Neuropsychiatric Inventory – Clinician Rating Scale (NPI-C)  SAMPLE ... 78 
Appendix G 
Mini-Mental State Examination (MMSE)  SAMPLE ................................... 96 
Appendix H 
Modified Alzheimer’s Disease Cooperative Study – Clinical Global
Impression of Change (mADCS-CGIC)  SAMPLE ....................................100 
Appendix I 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living
Inventory (ADCS-ADL)  SAMPLE ............................................................107 
Appendix J
Karolinska Sleepiness Scale (KSS)  SAMPLE ...........................................116 
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ABBREVIATIONS AND ACRONYMS 
5-HT2A 
5-hydroxytryptamine (serotonin) receptor 2A 
ACP-103 
pimavanserin tartrate (tartrate salt of the drug substance)  
AD 
Alzheimer’s disease 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
Inventory 
ADL 
activities of daily living 
AE 
adverse event 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CMAI 
Cohen-Mansfield Agitation Inventory 
CNS 
central nervous system 
CSR 
clinical study report 
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOS 
end-of-study 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GCAS 
Global Clinician Assessment of Suicidality 
hCG 
human chorionic gonadotropin 
HDL 
high density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
IRB 
Institutional Review Board 
IUD 
intrauterine device 
KSS 
Karolinska Sleepiness Scale 
LAR 
legally authorized representative 
LDL 
low density lipoprotein 
mADCS-CGIC 
modified Alzheimer’s Disease Cooperative Study - Clinical Global 
Impression of Change 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
ms 
Milliseconds 
NPI-C 
Neuropsychiatric Inventory-Clinician Rating Scale 
NPS 
neuropsychiatric symptoms 
PDP 
Parkinson’s disease psychosis 
PI 
Principal Investigator 
PRN 
pro re nata (as needed) 
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QD 
quaque die (once daily) 
QTcF 
Fridericia’s corrected QT 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMT 
Safety Management Team 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ZBI 
Zarit Burden Interview 
 
 
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1 BACKGROUND INFORMATION 
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Its clinical features 
include cognitive dysfunction, memory abnormalities, progressive impairment in activities of 
daily living (ADL), and a host of behavioral and neuropsychiatric symptoms 
(Cummings 2004; Lyketsos et al. 2011). While the diagnostic criteria for AD focus mostly on 
the related cognitive deficits, it is the behavioral and neuropsychiatric symptoms that are 
most troublesome for caregivers and lead to poor quality of life for patients 
(Herrmann and Lanctot 2007). These symptoms include agitation, aggressive behaviors, and 
psychosis. Agitation and aggression are a major cause of acute care inpatient hospitalizations 
(Soto et al. 2012) and pose a major challenge for AD patient care. Antipsychotics are 
frequently used, with limited efficacy and associated long-term safety risks. Considering the 
large number of AD patients, the increasing incidence, and the high prevalence of agitation in 
later stages of the disease, this unmet need for safe and effective treatments has a major 
public health impact (Peters et al. 2015). 
Neuropsychiatric symptoms (NPS) are now considered as core features of AD and may occur 
at any stage of the disease. Approximately 90% of AD patients develop NPS over the course 
of their disease (Lyketsos et al. 2002; Di Iulio et al. 2010). Neuropsychiatric symptoms are 
frequently associated with increased morbidity and are a leading cause of nursing home 
placement (Steele et al. 1990; Cohen-Mansfield et al. 1989). The prevalence of NPS 
increases and symptom profile evolves with disease progression (Lopez et al. 2003). 
Alzheimer’s disease patients with mild dementia often present with depression, anxiety, 
apathy, and irritability (Feldman et al. 2004), while patients in the advanced stages can 
exhibit agitation/aggression, delusions, hallucinations, and disinhibition (Lopez et al. 2003; 
Rockwood et al. 2015). 
Agitation is one of the most troublesome dementia symptoms, characterized by inappropriate 
verbal, vocal, or motor activity that can be independent of perceptible needs or confusion 
(Cohen-Mansfield and Billig 1986; Cummings et al. 2015b). These verbal and physical 
behaviors can deviate from social norms and include irrelevant vocalizations, screaming, 
cursing, restlessness, wandering, strange movements, and handling things inappropriately 
(Cohen-Mansfield et al. 1995). Such disruptive behaviors are a major source of stress for 
caregivers and loved ones and take a significant toll over time. Thus, the detection, 
management, and treatment of NPS including agitation, is critical in AD patient care 
(Lyketsos et al. 2006). 
In North America, there are currently no approved drugs for the treatment of agitation and/or 
aggression in AD. In the European Union (EU), risperidone is indicated for the short-term 
treatment of persistent aggression with a limited indication (Janssen-Cilag Ltd 2015). Since 
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NPS, especially agitation and aggression, are a major challenge in AD patient care, 
antipsychotics are frequently used off-label, despite their limited efficacy and associated 
long-term safety risks (Salzman et al. 2008). Antidepressants are also frequently used in the 
management of NPS in AD, despite lack of convincing efficacy (Finkel 2004; Koppel et al. 
2014; Teri et al. 2000). Adverse effects related to antipsychotics can include sedation, 
parkinsonism, gait disturbances, peripheral edema, chest infections, pneumonia, 
thromboembolic events, stroke, and death. Meta-analyses have confirmed this adverse events 
(AEs) pattern to be associated with atypical antipsychotics in people with dementia and 
suggested a marked increase in the risk of stroke and mortality (Ballard and Howard 2006). 
In addition, a doubling in the expected rate of cognitive deterioration was reported in a 2-year 
prospective, longitudinal study among patients treated with atypical antipsychotics 
(McShane et al. 2006). Moreover, a retrospective cohort study reported that traditional 
antipsychotics are as likely as atypical antipsychotics to increase the risk of death in elderly 
patients (Wang et al. 2005). 
Approved drugs for symptomatic treatment of AD have limited benefit on NPS. 
Cholinesterase inhibitors appear to have a small but measurable effect on depression, 
dysphoria, apathy/indifference, and anxiety but are probably not an effective short-term 
treatment for agitation or aggression (Gauthier et al. 2002). Memantine has shown 
inconsistent benefits in the treatment of irritability, agitation/aggression, and psychosis in AD 
patients (Gauthier et al. 2008; McShane et al. 2006; Wilcock et al. 2008). However, 
well-controlled randomized trials in moderate to severe AD patients with clinically 
significant agitation did not demonstrate a reduction in agitation with memantine 
(Ballard et al. 2015; Fox et al. 2012). Anticonvulsants, including valproic acid, have not 
shown positive results in recent studies (Amann et al. 2009; Tariot et al. 2005; 
Tariot et al. 2011). Citalopram has been shown to be effective in the treatment of agitation 
and aggression in AD, but can have significant safety concerns including QT prolongation 
and impaired cognition (Porsteinsson et al. 2014). An early clinical trial of 
dextromethorphan/quinidine showed improvement in agitation in patients with AD 
(Cummings et al. 2015a), but there may be safety concerns with quinidine including drug 
interactions and QT prolongation. 
Therefore, there remains an urgent clinical priority for effective and safe treatments of NPS 
in AD, including treatment of agitation/aggression. Ongoing efforts for identifying novel 
pharmacological treatments for AD agitation and aggression include development of 
non-dopaminergic, non-cholinergic, 5-hydroxytryptamine 2A (5-HT2A) receptor blocking 
compounds. Pimavanserin is one such compound that is a highly selective inverse agonist of 
the 5HT2A receptor that has been evaluated in Phase 3 clinical trials in Parkinson’s disease 
psychosis (PDP) and has been shown to improve psychosis, caregiver burden, and sleep 
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without causing sedation or other significant safety effects, and without a detrimental impact 
on cognition (Cummings et al. 2014). 
1.1 
Investigational Drug 
Pimavanserin (pimavanserin tartrate, or ACP-103) is the tartrate salt of the active moiety 
urea, N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N’-[[4-(2-
methylpropoxy)phenyl]methyl]-,(2R, 3R)-2,3-dihydroxybutanedioate (2:1) and is a novel 
small molecule designed to specifically block serotoninergic neurotransmission mediated by 
the 5-HT2A receptor. At higher doses pimavanserin may block 5HT2C receptors 
(Vanover et al. 2006). Polymorphisms of serotonin receptors and transporters have been 
implicated in AD agitation (Cummings and Zhong 2006). 
Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, histaminergic, or 
muscarinic receptors. Activity at these receptors has been implicated in a range of dose-
limiting side effects associated with existing antipsychotic drugs including cognitive dulling 
(Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased risk of mortality 
in elderly patients with dementia (Wang et al. 2005). On the basis of its novel receptor 
binding profile, pimavanserin may be effective in treating AD agitation and aggression, and 
may have added benefits in regard to overall tolerability relative to other antipsychotic 
agents. 
1.2 
Previous Clinical Experience 
Pimavanserin has been evaluated in 21 completed clinical studies and 4 additional studies are 
currently ongoing. As of 06 January 2016, an estimated total of 1237 subjects have been 
exposed to the investigational drug. These include 616 subjects with PDP. Across all 
populations and indications studied, a total of 764 subjects have received pimavanserin 
34 mg (i.e., 40 mg pimavanserin tartrate). From controlled studies in PDP, 498 subjects 
continued in long-term extension studies, and more than 250 subjects have received treatment 
for over a 1 year and more than 150 subjects for over 2 years. Total subject exposure in PDP 
exceeds 900 person-years. The longest reported continuous treatment with pimavanserin was 
for more than 10 years. 
Doses of up to 51 mg daily have been evaluated in PDP. Pimavanserin is considered to be 
generally safe and well tolerated. In single and multiple dose studies in healthy volunteers, 
the highest doses administered were 255 mg and 136 mg, respectively. Across all clinical 
studies of pimavanserin, the most frequently reported treatment-emergent AEs (TEAEs) were 
in the central nervous system (CNS), gastrointestinal (GI), and psychiatric systems. Most 
events were mild to moderate in intensity. The most common CNS events included dizziness 
(including postural), headache, and somnolence (drowsiness). Common GI disturbances 
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included dyspepsia, nausea, constipation, and vomiting; severe nausea and vomiting were 
dose limiting in a few cases. Reported psychiatric conditions included such events as 
agitation, insomnia, and confusional state. In controlled studies of pimavanserin in subjects 
with PDP, the most frequent TEAEs experienced by subjects in the pimavanserin 34 mg 
group compared with the placebo group were urinary tract infection (UTI) (7.4% 
pimavanserin 34 mg vs. 6.9% placebo), nausea (6.9% pimavanserin 34 mg vs. 4.3% placebo), 
peripheral edema (6.9% pimavanserin 34 mg, 2.2% placebo), fall (6.4% pimavanserin 34 mg 
vs. 9.1% placebo), and confusional state (5.9% pimavanserin 34 mg vs. 2.6% placebo). In the 
long-term open-label studies in subjects with PDP, the most frequent AEs include fall 
(29.3%), UTI (18.5%), hallucination (14.5%), decreased weight (12.4%), and confusional 
state (11.0%). It is difficult to interpret these incidence rates in the absence of a concurrent 
control group, but the overall incidence appears within what would be expected in subjects 
with the underlying neurodegenerative disease, psychosis, and advanced age. 
Clinical and non-clinical safety pharmacology studies of pimavanserin suggest a potential 
risk for QT prolongation. The magnitude of effect in humans has been assessed in a thorough 
QT study with doses of pimavanserin ranging from 17 to 68 mg and in the Phase 3 PDP 
program with a clinical dose of 34 mg. There was observed an average prolongation of 
approximately 5-8 milliseconds (ms). No clinically significant patterns have been observed in 
serious adverse events (SAEs) and there has been no evidence of pimavanserin-related 
laboratory abnormalities. As of 30 October 2015, 67 subjects have died during study 
participation with the majority of deaths considered not related or unlikely related to study 
drug. Five of these deaths occurred in 6-week double-blind studies (1 subject received 
placebo, 1 subject received 8.5 mg pimavanserin, and 3 subjects received 34 mg 
pimavanserin), and 62 deaths occurred in the multi-year, long-term open-label extension 
studies where the majority of subjects had been treated with pimavanserin for greater than 
2 years. 
Additional information is provided in the Investigator’s Brochure. 
1.3 
Study Rationale 
Given the various adverse consequences of AD, an active therapeutic intervention is needed 
that could effectively manage symptoms of agitation and aggression without increasing the 
risk for sedation, hematologic disorders, significant cardiovascular events, infections, or 
mortality in this older subject population. 
Atypical antipsychotics are often used off-label for the treatment of agitation and aggression 
in AD, despite the safety risks. The activity of pimavanserin as a selective 5-HT2A inverse 
agonist may be beneficial for the treatment of AD subjects with agitation and aggression 
without many of the AEs associated with typical and atypical antipsychotics. A variety of 
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neurotransmitters and their receptors, including dopamine (e.g., D1, D2, D3), histamine (H1), 
acetylcholine (e.g., M1, M3, M4), epinephrine (e.g., α1A, α2B, α2C) and serotonin (e.g., 
5-HT2A, 5-HT2B, 5-HT2C) are targeted by the typical and atypical antipsychotics, which may 
also contribute to their associated AEs. The selective activity of pimavanserin at the 5-HT2A 
receptor could avoid many of the off-target side effects while providing clinical efficacy. 
The parent study, ACP-103-032, is designed to evaluate pimavanserin for the treatment of 
agitation and aggression in AD and incorporates methods to facilitate an appropriate 
assessment (Soto et al. 2015). The purpose of this study, ACP-103-033, is to collect long-
term safety and efficacy data from subjects after exposure to pimavanserin for a total duration 
of up to 52 weeks (~64 weeks total for subjects who received pimavanserin in Study 
ACP-103-032). The primary and safety measures will assess the safety and tolerability of 
pimavanserin; the exploratory efficacy measures will assess the long-term efficacy of 
pimavanserin in treatment of agitation and aggression and the effect on caregiver burden. 
2 OBJECTIVES 
The purpose of this study is to evaluate the safety and tolerability of pimavanserin treatment 
for up to 52 weeks of exposure (~64 weeks total for subjects who received pimavanserin in 
Study ACP-103-032), in subjects with probable AD. 
2.1 
Primary Objective and Endpoints 
2.1.1 
Primary Objective 
To evaluate the safety and tolerability of pimavanserin after 52 weeks of treatment in subjects 
with probable AD who have symptoms of agitation and aggression. 
2.1.2 
Primary Endpoint 
 Treatment emergent adverse events (TEAEs) 
2.1.3 
Safety Endpoints 
 Serious AEs (SAEs) and withdrawals due to AEs 
 Global Clinician Assessment of Suicidality (GCAS) 
 Clinically important changes from Baseline in vital sign measurements, weight, 
clinical laboratory assessments, physical examinations, and electrocardiograms 
(ECGs) 
2.2 
Exploratory Objectives and Endpoints 
2.2.1 
Exploratory Objectives 
To evaluate the persistence of the effects of pimavanserin treatment on: 
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 Agitation and aggression  
 Caregiver burden 
 The clinician’s global assessment of treatment benefit 
 Other neuropsychiatric symptoms 
 Cognition 
 Functional status 
 Sleep and daytime wakefulness  
2.2.2 
Exploratory Endpoints 
 Change from Baseline in Cohen-Mansfield Agitation Inventory (CMAI) total score  
 Change from Baseline in Zarit Burden Interview (ZBI) total score  
 Modified Alzheimer’s Disease Cooperative Study - Clinical Global Impression of 
Change (mADCS-CGIC) agitation score  
 Change from Baseline in Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C) 
combined agitation and aggression domain scores 
 Change from Baseline in NPI-C total score  
 Change from Baseline in NPI-C individual domain scores 
 Change from Baseline in Mini-Mental State Examination (MMSE) score 
 Change from Baseline in Karolinska Sleepiness Scale (KSS) score 
 Change from Baseline in CMAI subscale scores  
 Change from Baseline in Alzheimer’s Disease Cooperative Study - Activities of Daily 
Living Inventory (ADCS-ADL) score 
3 STUDY DESIGN 
3.1 
Overall Study Design 
This study is an open-label extension study of the safety and tolerability of pimavanserin for 
the treatment of agitation and aggression in subjects with probable AD 
(McKhann et al. 2011). This study will be conducted as a 52-week, open-label, flexible-dose 
extension of Study ACP-103-032. Subjects in Study ACP-103-033 must have completed 
ACP-103-032 and must meet eligibility criteria. 
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Study ACP-103-033 subjects must be consented prior to the final procedures being 
performed for Study ACP-103-032 at Week 12. Procedures from the Week 12 visit of 
Study ACP-103-032 will be carried over to the ACP-103-033 study to be included as baseline 
information and this visit will be considered the Baseline Visit (Visit 1) of the ACP-103-033 
study. 
Study periods: 
 Open-label treatment period (Baseline through 52 weeks of treatment) 
 Safety follow-up period (~30 days after the last dose of study drug) 
Treatment Period (Baseline through Week 52) 
All subjects will receive once daily (QD) doses of pimavanserin (active study drug) over 
52 weeks of treatment, starting with 20 mg a day. At the Week 2 visit, the pimavanserin 
20 mg dose may be increased to 34 mg a day based on the Investigator’s assessment of 
clinical response. The Investigator may then adjust the dose from 20 mg to 34 mg or from 
34 mg to 20 mg at any visit based on clinical response. A dose change at a time other than at 
a scheduled clinic visit will require an unscheduled visit to dispense the appropriate dose of 
study drug. Unscheduled clinic visits may occur as needed. 
During the Treatment Period, clinic visits will be conducted at Baseline and Weeks 2, 4, 8, 
12, 20, 28, 36, 44, and 52, or upon early termination (ET) from the study. 
It is recommended that the study drug be taken at approximately the same time each day.  
Doses of concomitant or over-the-counter medications should not exceed those indicated for 
Permitted and Prohibited Concomitant Therapy and Rescue Medication (see Section 5.6).  
Follow-up of Study Completers 
A follow-up safety assessment will be conducted via telephone approximately 30 days after 
the last dose of study drug for subjects who complete the 52-week treatment period and for 
those who discontinue prematurely from the study. 
3.1.1 
Study Duration 
The duration of participation for individual subjects will be up to approximately 56 weeks: 
each subject will participate in a 52-week treatment period followed by an approximately 
30-day follow-up period. The end of the clinical trial will be when the last subject completes 
the last scheduled assessment (i.e., 30-day follow-up). 
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3.2 
Dose Rationale  
In previous studies of pimavanserin in the PDP population, a dose of 34 mg of pimavanserin 
has demonstrated a consistent signal of efficacy across a number of measures, including the 
Scale for the Assessment of Positive Symptoms (SAPS), Clinical Global Impression - 
Improvement (CGI-I), Scale for Outcomes in Parkinson 's disease-Sleep Scale 
(SCOPA-Sleep) nighttime sleep measure and caregiver burden scale. Additionally, long-term 
open-label studies of pimavanserin in PDP have demonstrated that pimavanserin is safe and 
tolerable at doses of 34 mg and 51 mg. Parkinson’s disease and AD have similar 
neuropsychiatric symptoms that include psychosis, agitation, and other behavioral problems 
that can have a heterogeneous presentation. These symptoms can be responsive to treatment 
with antipsychotics; pimavanserin has been approved for treatment in PDP in the United 
States and could show benefit for the treatment of other symptoms. Thus, a dose of 34 mg 
pimavanserin that has been shown to be effective in the treatment of PDP 
(Cummings et al. 2014) is included as the high dose in this study. A dose of 20 mg 
pimavanserin is included as a possible low dose for the treatment of agitation and aggression 
in patients with AD. The dose of pimavanserin can be adjusted to 20 mg or 34 mg based on 
clinical judgment.  
3.3 
Number of Subjects 
Up to approximately 111 male and female subjects with probable AD who have symptoms of 
agitation and aggression and who have completed Study ACP-103-032 and meet the 
eligibility criteria for ACP 103-033, as outlined in Section 4.1, will enroll in this study.  
3.4 
Study Procedures 
3.4.1 
Site Initiation Procedures 
Before a subject may be enrolled in the study at a site, ACADIA and/or designee must obtain 
a copy of essential documents for that site including the following: 
 Institutional Review Board (IRB) or Ethics Committee (EC) approval of the protocol 
 IRB- or EC-approved Informed Consent Form (ICF) 
 Financial disclosure form(s), as applicable 
 Other documents required by local regulations, as applicable 
Each subject and their study partner/caregiver must sign the approved ICF prior to enrolling 
in the study. Each subject will have the same subject identification number in this study as 
they did in Study ACP-103-032. 
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3.4.2 
Schedule of Events and Assessments 
The Schedule of Events and Assessments for the study is presented in Appendix A. Clinic 
visits may be split over multiple days within the windows specified in the Schedule of Events 
and Assessments, if necessary. 
3.4.3 
Visit 1 (Baseline) 
Study ACP-103-033 subjects must be consented prior to the final procedures being 
performed for Study APC-103-032 at Week 12. Procedures from the Week 12 visit of 
Study ACP-103-032 will be carried over to the ACP-103-033 study to be included as baseline 
information and this visit will be considered the Baseline Visit (Visit 1) of the ACP-103-033 
study. 
At the Baseline visit of Study ACP-103-033, study drug will be dispensed to the subject to 
take home. The subject and their study partner/caregiver will be provided instructions to take 
the first dose of study drug on the following day. It is recommended that the subject take the 
study drug at approximately the same time each day. 
Baseline evaluations will include the following: 
 Physical examination 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight  
 12-lead ECG (single recording) 
 Laboratory profiles (hematology, serum chemistry, and urinalysis [if able]) 
 Urine pregnancy test for all women of childbearing potential 
 CMAI 
 ZBI 
 NPI-C all domains  
 MMSE 
 KSS 
 mADCS-CGIC 
 ADCS-ADL 
 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
 Dispense study drug 
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3.4.4 
Visit 2 (Week 2) 
Subjects will have the following procedures completed: 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight 
 CMAI 
 ZBI 
 NPI-C agitation and aggression domains only 
 mADCS-CGIC 
 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
 Dispense study drug 
 Study drug accountability  
3.4.5 
Visit 3 (Week 4) 
Subjects will have the following procedures completed: 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight 
 12-lead ECG (single recording) 
 Laboratory profiles (hematology, serum chemistry, and urinalysis [if able]) 
 Urine pregnancy test for all women of childbearing potential 
 CMAI 
 ZBI 
 NPI-C agitation and aggression domains only 
 MMSE 
 mADCS-CGIC 
 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
 Dispense study drug  
 Study drug accountability  
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3.4.6 
Visit 4 (Week 8) 
Subjects will have the following procedures completed: 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight 
 CMAI 
 ZBI 
 NPI-C agitation and aggression domains only 
 MMSE 
 mADCS-CGIC 
 Record concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
 Dispense study drug  
 Study drug accountability  
3.4.7 
Visits 5, 6, 7, 8, and 9 (Weeks 12, 20, 28, 36, and 44) 
Subjects will have the following procedures completed: 
 Physical examination (Visit 5 only) 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight 
 12-lead ECG (single recording; Visits 5 and 7 only) 
 Laboratory profiles (hematology, serum chemistry, and urinalysis [if able]; Visits 5 and 
7 only) 
 Urine pregnancy test for all women of childbearing potential 
 CMAI 
 ZBI 
 NPI-C all domains (Visits 5 and 7 only) 
 MMSE 
 KSS (Visits 5 and 7 only)  
 mADCS-CGIC 
 ADCS-ADL (Visits 5 and 7 only) 
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 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
 Dispense study drug  
 Study drug accountability  
3.4.8 
Visit 10 (Week 52 [End-of-Study/Early Termination]) 
Subjects will have the following procedures completed: 
 Physical examination 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight 
 12-lead ECG (single recording) 
 Laboratory profiles (hematology, serum chemistry, and urinalysis [if able]) 
 Urine pregnancy test for all women of childbearing potential 
 CMAI 
 ZBI 
 NPI-C all domains 
 MMSE 
 KSS 
 mADCS-CGIC 
 ADCS-ADL 
 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
 Study drug accountability 
3.4.9 
Unscheduled Visits 
Subjects will have the following procedures completed: 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
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 CMAI and mADCS-CGIC (if the unscheduled visit is to change dose) 
 Dispense study drug (if dose changed) 
 Study drug accountability (if dose changed)  
3.4.10 Visit 11 (30-day Safety Follow-up, Week 56, Telephone) 
 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 GCAS 
4 SELECTION OF SUBJECTS AND CRITERIA FOR WITHDRAWAL 
4.1 
Selection of Subjects 
Subjects must fulfill all of the following inclusion and none of the exclusion criteria 
(Sections 4.1.1 and 4.1.2, respectively) to be eligible for participation in the study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s participation in the trial, it is discovered that the subject 
did not meet all eligibility criteria, s/he will be discontinued, unless the discontinuation 
presents an unacceptable medical risk. The justification to allow the subject to continue in the 
trial will be made by the Sponsor, with medical input from the Investigator, and will be 
documented. If allowed to remain in the trial, this will be reported as a major protocol 
deviation and not a waiver. All follow-up safety assessments must be completed and 
documented as outlined in the protocol. 
4.1.1 
Inclusion Criteria 
1. Can understand the nature of the trial and protocol requirements and provide signed 
informed consent and can understand and sign other forms necessary for participation 
in the trial (e.g., the Health Insurance Portability and Accountability Act [HIPAA] 
authorization form in the United States). The following requirements for consent must 
be met: 
○ from the subject, if the subject is deemed competent to provide informed consent 
○ from an appropriate person according to national and local regulations (e.g., the 
subject’s legally authorized representative [LAR] with the subject’s assent), if the 
subject is deemed not competent to provide informed consent 
2. Lives at home or in an assisted living or care facility (but has the capacity to visit the 
clinic as an outpatient).  
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3. Has a designated study partner/caregiver (e.g., relative, housemate, close personal 
friend, or professional caregiver) who is in contact with the subject at least 3 times a 
week on 3 separate days. The study partner/caregiver should: 
○ be willing and able to accompany the subject to all clinic visits, 
○ be capable of routinely monitoring and reporting study drug use, 
○ be regarded by the Investigator as sufficiently informed to report accurately on the 
subject’s behavioral and functional status. 
4. The subject’s study partner/caregiver provides written agreement that they understand 
the study, including the role of the study partner/caregiver and will participate in the 
study  
5. Both subject and study partner/caregiver are fluent in and able to read the local 
language in which study assessments are administered at the clinical site 
6. Both subject and study partner/caregiver are willing and able to participate in all 
scheduled evaluations and complete all required tests 
7. Must complete the Week 12 visit in Study ACP-103-032 while continuing to take 
his/her assigned dose of blinded study drug 
8. If female, must be of non-childbearing potential (defined as either surgically sterilized 
or at least 1 year postmenopausal) or must agree to use a clinically acceptable method 
of contraception (e.g., oral, intrauterine device [IUD; diaphragm], injectable, 
transdermal or implantable contraception) or abstinence during the study, and 1 month 
following completion of the study. Females of childbearing potential must have a 
negative urine human chorionic gonadotropin (hCG) pregnancy test at Baseline. 
4.1.2 
Exclusion Criteria 
1. Is participating in another clinical trial (other than Study ACP-103-032) of any 
investigational drug, device, or intervention  
2. The Investigator determines that enrollment in the study would be detrimental to a 
subject’s well-being 
3. The Investigator becomes aware of an impending and unexpected change in the 
subject’s living situation (e.g., change in caregiver, change in facility, moving from 
home to facility, moving from one family member or caregiver’s home to another) 
that s/he judges may cause a major disruption in the subject’s behavior 
4. Subject or study partner/caregiver has an uncorrected medical condition (e.g., hearing, 
vision impairments) that would impair the ability to perform the study assessments. 
5. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for 
the study 
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6. Subject was significantly non-compliant in Study ACP-103-032 
7. Subject has had a QRS interval <120 ms and whose Fridericia’s corrected QT interval 
(QTcF) is >460 ms at baseline OR subject has had a QRS interval ≥120 ms and QTcF 
is >480 ms at Baseline 
8. Has clinically significant laboratory abnormalities that in the judgment of the 
Investigator would jeopardize the safe participation of the subject in the study 
9. Subject has become bedridden or has any significant medical condition that is 
unstable and that would either: 
○ place the subject at undue risk from study drug or undergoing study procedures; 
or 
○ interfere with the interpretation of safety or efficacy evaluations performed during 
the course of the study  
10. Subject is receiving skilled nursing care for any medical condition other than 
dementia (skilled nursing care includes procedures that can only be administered by a 
registered nurse or doctor, such as [but not limited to] intravenous administration of 
medication, procedures related to insertion or care of suprapubic catheters, and 
nasopharyngeal/tracheostomy aspiration)  
11. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 or 4 based on 
Investigator’s assessment of behavior since the last assessment 
4.2 
Subject Withdrawal 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 
If consent has been given by a LAR because the subject is not competent to provide informed 
consent, the LAR has the right to withdraw the subject from the study at any time, and for 
any reason, without prejudice to the subject’s future medical care or any penalty or loss of 
benefits to the LAR. 
The study partner/caregiver has the right to withdraw his or her agreement to participate in 
the study at any time, and for any reason, without prejudice to the subject’s future medical 
care or any penalty or loss of benefits to the caregiver. If the study partner/caregiver 
withdraws agreement to participate, the subject must be discontinued unless another suitable 
study partner/caregiver is available to sign the agreement to participate. 
Subjects may be discontinued or withdrawn from the study for a number of reasons, 
including but not limited to those listed below: 
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 Adverse events(s) (serious or non-serious) 
 The Investigator becomes aware of an impending and unexpected change in the 
subject’s living situation (e.g., change in caregiver, change in facility, moving from 
home to facility, moving from one family member or caregiver’s home to another) that 
s/he judges may cause a major disruption in the subject’s behavior 
 The Investigator determines that continuation in the study would be detrimental to a 
subject’s well-being 
 At the discretion of the Sponsor 
 Subject fails to comply with protocol requirements 
 Voluntary withdrawal of consent by subject or subject’s LAR (wherever possible, the 
reason for withdrawal of consent should be collected) 
 Subject is lost to follow-up 
 Female subject becomes pregnant 
Every effort should be made to complete the end of study (EOS)/early termination (ET) visit 
should a subject discontinue prematurely from the study. 
If a subject is lost to follow-up, every effort should be made to phone the subject’s caregiver 
approximately 30 days after last known contact with the subject in order to assess the 
subject’s current status. All phone contact with the caregiver should be documented. 
For subjects who continue to be followed for safety, SAEs should continue to be reported as 
described in Section 7.5.1. 
If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow the subject until the AE resolves or until the Investigator, in conjunction 
with ACADIA, deems the AE to be chronic or stable. 
All SAEs will continue to be followed until EOS/ET visit or until such events have resolved 
or the Investigator, in conjunction with ACADIA, deems them to be chronic or stable. 
4.2.1 
Criteria for Subject Withdrawal 
A subject may withdraw from the study at any time and for any reason without penalty or 
loss of benefits to which the subject is otherwise entitled. 
Subjects may be discontinued or withdrawn from the study as noted in Section 4.2. 
Should a subject request or decide to withdraw, all efforts will be made to complete and 
report observations as thoroughly as possible up to the date of withdrawal, including the 
evaluations specified at the EOS/ET visit as outlined in Appendix A. Every attempt will be 
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made to complete the 30-day safety follow-up phone call for all subjects who withdraw 
prematurely. All information will be reported on the applicable pages of the electronic case 
report form (eCRF). 
5 TREATMENTS ADMINISTERED 
5.1 
Identity of Investigational Product 
Drug 
Administration 
Form 
Total Dose 
Provided as 
Route of 
Administration 
Pimavanserin 
Tablet 
20 mg 
2×10 mg tablets 
Oral 
Pimavanserin 
Tablet 
34 mg 
2×17 mg tablets 
Oral 
 
5.2 
Administration of Study Drug 
All subjects will receive once daily (QD) doses of pimavanserin (active study drug) over 
52 weeks of treatment, starting with 20 mg a day for the first 2 weeks. Dose adjustment will 
be allowed thereafter based on the Investigator’s assessment of clinical response (see 
Section 5.4). 
It is recommended that the subject take the study drug at approximately the same time each 
day. Study drug can be taken with or without food consumption. 
5.3 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol. It must be reported, irrespective of outcome even if toxic effects 
were not observed. An overdose is considered an AE only if there are symptoms associated 
with the event. All events of overdose need to be captured as protocol deviations. 
5.4 
Dosage Adjustments 
Dose adjustments will be allowed for pimavanserin based on clinical response. At the Week 2 
visit (Visit 2), the pimavanserin 20 mg starting dose may be increased to 34 mg a day based 
on the Investigator’s assessment of clinical response. The Investigator may adjust the dose 
from 20 mg to 34 mg or from 34 mg to 20 mg at any visit based on clinical response. A dose 
change at a time other than at a scheduled clinic visit will require an unscheduled visit to 
dispense the appropriate dose of study drug.  
5.5 
Method of Assigning Subjects to Treatment Groups 
Subjects who have signed the ICF and are enrolled into the study will be entered into the 
electronic data capture (EDC) system. Subjects will have the same subject identification 
number in this study as they had in Study ACP-103-032. The subject identification number 
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consists of a 3-digit site number followed by a unique 3-digit number. Subjects will keep this 
same subject identification number throughout the study. 
5.6 
Concomitant Medications 
All ongoing concomitant medications will be captured from the preceding double-blind study 
(ACP-103-032) and will be recorded from Baseline through the EOS/ET visit. 
In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator. 
The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. The Sponsor and Investigator will confer to determine whether it is appropriate 
to continue such a subject in the trial if a prohibited medication is prescribed. 
Subjects who take prohibited concomitant medications during the trial will be discontinued, 
unless the discontinuation presents an unacceptable medical risk. The justification to allow 
the subject to continue in the trial will be made by the Sponsor with medical input from the 
Investigator, and will be documented. If allowed to remain in the trial, this will be reported as 
a major protocol deviation and not a waiver. All follow-up safety assessments must be 
completed and documented as outlined in the protocol. 
5.6.1 
Permitted Concomitant Medications 
All concomitant antidepressants, cholinesterase inhibitors, memantine, and other permitted 
medications should remain at a stable dose throughout the study, if possible. 
5.6.2 
Prohibited and Restricted Medications 
Restrictions for concomitant medications should be followed through the EOS/ET visit as 
specified in Appendix B and Appendix C. These appendices do not constitute an exhaustive 
list and any questions regarding prohibited and restricted medications should be discussed 
with the Medical Monitor or appropriate designee. 
Use of medications that could interfere with study conduct or any questions regarding 
prohibited and restricted concomitant medications should be reviewed and/or discussed with 
the Medical Monitor or appropriate designee. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix B. 
5.6.3 
Rescue Medications 
At the discretion of the Investigator, lorazepam (a benzodiazepine) may be used as a rescue 
medication for the management of agitation and/or aggression. Any use or increase in dose of 
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lorazepam must be documented. At a maximum dose of up to 2 mg per 24-hour period, 
lorazepam will be allowed as rescue medication only on an intermittent or PRN basis, and 
should not be taken within 24 hours prior to the next study visit. Lorazepam may not be used 
for more than 10 cumulative days in any 4-week period. If lorazepam is not available, 
another intermediate-acting benzodiazepine may be used at doses equivalent to lorazepam 
doses. 
5.7 
Blinding 
This study will be conducted as an open-label study. 
5.8 
Investigational Drug Handling 
5.8.1 
Test Article 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin tablets include the active 
compound (pimavanserin) and the following excipients:
 
 
Pimavanserin will be provided as 10 mg and 17 mg strength tablets.  
Pimavanserin used for the tablets are manufactured under current Good Manufacturing 
Practices compliance by
 
5.8.2 
Investigational Drug Packaging 
Study drug will be supplied as individual uniquely numbered bottles. Each bottle contains 
60 tablets and is sufficient for 4 weeks of treatment. Each tablet contains pimavanserin 10 mg 
or 17 mg. 
5.8.3 
Receipt of Investigational Drug Supplies 
The Investigator and/or study staff is responsible for taking an inventory of each shipment of 
investigational drug received and comparing it with the accompanying drug accountability 
report/material shipping form. The Investigator or study staff member will verify the 
accuracy of the information on the form, sign and date it, and return the form to the Sponsor 
or designee. All investigational drug supplied is for use in this study only and should not be 
used for any other purpose. 
5.8.4 
Storage of Investigational Drug 
The investigational drug must be kept at 15°C to 30°C (59°F to 86°F) [see USP Controlled 
Room Temperature] in a secure area with restricted access and according to applicable 
country, state, and federal regulations. Neither the Investigator, nor the pharmacist, nor any of 
his/her designees may provide investigational drug to any person not participating in the 
study. 
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5.8.5 
Investigational Drug Dosing 
Study drug will be dispensed to the subject to take home at the Baseline Visit. The subject 
and their study partner/caregiver will be provided instructions to take the first dose of study 
drug on the following day. It is recommended that the subject take the study drug at 
approximately the same time each day as a single, oral dose. Study drug can be taken with or 
without food consumption. 
At the Week 2 visit (Visit 2) and thereafter, the dose of pimavanserin may be adjusted based 
on the Investigator’s assessment of clinical response (see Section 5.4). Dose adjustments 
must be recorded and include date of change, dose, and reason for change. At each visit 
where drug is dispensed, previously dispensed unused drug and any empty containers are to 
be returned to the Investigator. 
5.8.5.1 
Treatment Period 
At Baseline, subjects will be provided with study drug to take home. The subject and their 
study partner/caregiver will be provided instructions to take the first dose of study drug on 
the following day. It is recommended that the subject take the study drug at approximately 
the same time each day. 
Additional study drug will be provided according to the Schedule of Events and Assessments 
(Appendix A) or at unscheduled study visits. Investigational drug supplies will be labeled in 
accordance with all applicable guidelines and/or regulations. 
5.8.6 
Record of Dispensing 
Accurate recording of all investigational drug administration for individual subjects will be 
made in the appropriate section of the subject’s eCRF as well as in the site investigational 
drug dispensing and reconciliation form. Drug accountability records must be updated as 
subjects are enrolled and throughout the conduct of the study. 
5.8.7 
Accountability 
The Investigator or designee will keep current and accurate records of the investigational 
drug product dispensed, used, and returned for each subject to assure the health authority and 
Sponsor that the investigational drug is being handled appropriately. Subjects should be 
instructed to return all packaging, bottles, and unused medication to the Investigator at 
scheduled and unscheduled clinic visits when drug is dispensed and at the EOS/ET visit. 
At appropriate intervals during the study, investigational drug reconciliation will be 
performed by the Sponsor representative who may return appropriate used and unused 
investigational drug and used and unused packaging to the Sponsor’s designee for 
destruction. 
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At the conclusion of the study, final investigational drug reconciliation will be conducted at 
the site. Final investigational drug accountability documentation will be maintained at both 
the site and at ACADIA. Any remaining unused investigational drug and all used and unused 
packaging will be sent back to the Sponsor’s designee for destruction. Documentation of 
investigational drug destruction will be recorded and maintained by both ACADIA and the 
Sponsor’s designee. 
6 EFFICACY AND SAFETY ASSESSMENTS 
6.1 
Efficacy Assessments 
The following efficacy endpoints will be assessed in this study using the measures described 
in this section: CMAI, ZBI, NPI-C, MMSE, mADCS-CGIC, KSS, and ADCS-ADL. 
Of the measures listed in the following sections, the CMAI should be completed first, followed 
by completion of the other instruments. For each scale, the time period assessed will be from 
the time of the last scheduled assessment. All Baseline assessments that are referred to in the 
following sections will be carried over from the Week 12 visit of Study ACP-103-032, where 
applicable. 
6.1.1 
Cohen-Mansfield Agitation Inventory  
The CMAI was developed to assess the frequency of manifestations of agitated behaviors in 
elderly persons (Cohen-Mansfield 1989; see Appendix D). 
The CMAI is a 29-item scale designed to systematically assess agitation, rated on a 7 point 
(1-7) scale of frequency. Subjects are rated by their primary caregiver regarding the 
frequency with which they manifest physically aggressive, physically non-aggressive and 
verbally agitated behaviors. The CMAI may be self-administered (by a caregiver) or, as in 
this study, it may be completed by interview. Ratings are inclusive of the 2 or 4 weeks prior 
to the administration of the scale. Separate scores for agitation and aggression behaviors can 
be derived from the CMAI in addition to the total score. 
The CMAI will be performed at Baseline (Day 1) and at all scheduled clinic visits. 
6.1.2 
Zarit Burden Interview  
The ZBI was designed to assess the stresses experienced by caregivers of patients with 
dementia (Zarit et al. 1980; see Appendix E). The ZBI can be self-reported or, as in this 
study, administered as an interview. Caregivers are asked to respond to a series of 
22 questions about the impact of the patient’s disabilities on their life. For each item, 
caregivers are to indicate how often they felt that way (never, rarely, sometimes, quite 
frequently, or nearly always). The ZBI will be administered at Baseline (Day 1) and at 
Weeks 2, 4, 8, 12, 20, 28, 36, 44, and 52 (EOS/ET).  
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Note: Professional caregivers do not complete this form.  
6.1.3 
Neuropsychiatric Inventory – Clinician Rating Scale  
The NPI-C (de Medeiros et al. 2010) was developed to assess psychopathology in patients 
with dementia (Appendix F). The NPI-C evaluates NPS across multiple behavioral domains, 
as in the NPI (Cummings et al. 1994), as a standalone measure for specific NPS domains 
(e.g., dysphoria, agitation), or as a combination of both (presence of NPS across domains 
plus particular focus on one or more specific domains). The score of each item, if present, is 
clinically evaluated based on the symptom frequency, severity/intensity, and distress of a 
behavior. Multiple behaviors within a category are rated and included in the score. The 
NPI-C version of the NPI scale was designed to be administered by the clinician to the 
caregiver and can be administered to a professional caregiver or other involved person as 
long as they have detailed knowledge of the subject’s behavior. If a subject is not able to 
provide reliable information (e.g., due to cognitive impairment, or is uncooperative), the 
NPI-C should be rated by the clinician using all other available information including 
behavioral observations.  
The complete NPI-C (i.e., all domains) will be performed at Baseline, Weeks 12, 28, and 
52 (i.e., Visits 1, 5, 7, and 10 [EOS/ET]). The agitation and aggression domains of the NPI-C 
alone will be performed at Weeks 2, 4, and 8 (i.e., Visits 2, 3, and 4). 
6.1.4 
Mini–Mental State Examination 
The MMSE is a brief 30-point questionnaire that is used to quantitatively assess cognition 
(Folstein et al. 1975; see Appendix G). The MMSE includes simple questions and problems 
in a number of areas: the time and place of the test, repeating lists of words, arithmetic, 
language use and comprehension, and copying a drawing. It can be used to screen for 
cognitive impairment, to estimate the severity of cognitive impairment at a given point in 
time, to follow the course of cognitive changes in an individual over time, and to document 
an individual’s response to treatment. The MMSE will be administered at Baseline (Visit 1) 
and at Weeks 4, 8, 12, 20, 28, 36, 44, and 52 (i.e., Visits 3, 4, 5, 6, 7, 8, 9 and 10 [EOS/ET]). 
6.1.5 
Modified Alzheimer’s Disease Cooperative Study - Clinical Global Impression-
Change 
The mADCS-CGIC scale (Schneider et al. 1997) will be used to allow the Investigator to 
determine the subject’s overall clinical condition as it relates to their symptoms of agitation 
and aggression, and to address the clinical significance of changes from Baseline in other 
psychometric measures (Appendix H). The mADCS-CGIC interview will be performed by 
the Investigator or a medically qualified rater. After completion of the interview, the rater will 
be asked to rate the subject’s symptoms of agitation and aggression relative to the Baseline 
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interview from the parent study (ACP-103-032), using a standardized 7-point 
scale (1=marked improvement to 7=marked worsening). 
The mADCS-CGIC will be administered at Baseline (Visit 1) and at all scheduled clinic 
visits. 
6.1.6 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living Inventory  
The ADCS-ADL is an inventory to assess activities of daily living in subjects with AD 
(Galasko et al. 1997; see Appendix I). This is a caregiver-rated questionnaire that includes 
23 items related to subject ADLs. The instrument assesses functional capacity across a large 
spectrum of dementia severity. The ADCS-ADL will be administered at Baseline (Visit 1) 
and at Weeks 12, 28, and 52 (i.e., Visits 5, 7, and 10 [EOS/ET]). 
6.1.7 
Karolinska Sleepiness Scale  
The KSS is a self-reported subjective measure of a subject's level of drowsiness 
(Akerstedt and  Gillberg 2009; Johns 2009; see Appendix J). With the modified version 
(Geiger Brown et al. 2014) respondents must choose which of 9 statements most accurately 
describes their level of sleepiness over a period of time, which for this study will be “on 
average over the previous week” (see Appendix J). The KSS will be administered at Baseline 
(Visit 1) and at Weeks 12, 28, and 52 (i.e., Visits 5, 7, and 10 [EOS/ET]). 
6.2 
Safety Assessments 
Standard clinical evaluations and objective measures will be employed to monitor and assess 
safety during the conduct of this trial. Results of safety assessments will be used to identify 
any investigational drug-related effects or trends after the trial is completed. Furthermore, 
results of the safety assessments will be used during the conduct of the trial to monitor and 
protect the safety of enrolled subjects. Information regarding safety monitoring can be found 
in the sections below. 
Safety and tolerability assessments for all subjects will include: medical and medication 
history including AD history, physical examinations, vital signs, weight, ECGs, suicidal 
ideation and behavior, and safety laboratory evaluations. 
All Baseline assessments that are referred to in the following sections will be carried over 
from the Week 12 visit of Study ACP-103-032, where applicable. 
6.2.1 
Medical and Medication History 
Medical and medication history will be carried over from the preceding double-blind study 
(ACP-103-032). 
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6.2.2 
Alzheimer’s Disease History 
A thorough subject history specific to their diagnosis of probable AD will be carried over 
from the preceding double-blind study (ACP-103-032). 
6.2.3 
Physical Examinations 
Physical and neurological examinations will be conducted at Baseline (Visit 1) and Weeks 12 
and 52 (i.e., Visits 5 and 10 [EOS/ET]). The examinations may include a review of all body 
systems (urogenital examination is required only if indicated) and should include a 
neurological examination (e.g., level of consciousness, speech, cranial nerves [including 
pupil equality and reactivity], motor assessment, sensory assessment, coordination, gait, 
reflexes, and Romberg test). 
6.2.4 
Vital Signs 
Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) will be performed at Baseline (Visit 1) and at all scheduled visits. 
6.2.5 
Weight 
Weight will be measured at Baseline (Visit 1) and at all scheduled visits. 
6.2.6 
Electrocardiograms 
A 12-lead ECG (single recording) will be performed at Baseline (Visit 1) and at Weeks 4, 12, 
28, and 52 (i.e., Visits 3, 5, 7, and 10 [EOS/ET]). 
6.2.7 
Safety Laboratory Evaluations 
Safety laboratory evaluations will be analyzed by a Central Laboratory. Blood and urine 
samples for safety laboratory evaluations will be collected at Baseline (Visit 1) and Weeks 4, 
12, 28, and 52 (i.e., Visits 3, 5, 7, and 10 [EOS/ET]). 
Females of child bearing potential must agree to use a clinically acceptable method of 
contraception (e.g., oral, intrauterine device [IUD; diaphragm], injectable, transdermal or 
implantable contraception) or abstinence during the study, and 1 month following the last 
dose of study medication. Abstinence as a method of contraception defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. 
This option is usually made for a specific moral, religious, legal, or health reason. If 
heterosexual intercourse does occur, an appropriate method of birth control is required. For 
all female subjects of childbearing potential, a urine pregnancy test will be performed at 
Baseline (Visit 1) and at Weeks 4, 12, 20, 28, 36, 44, and 52 (i.e., Visit 3, 5, 6, 7, 8, 9, and 10 
[EOS/ET]). Pregnancy tests must be negative at Baseline for study entry and at the Weeks 4, 
12, 20, 28, 36, and 44 visits to continue in the study. 
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Note: A urinalysis is not applicable for those subjects who are unable to provide a urine 
sample (e.g., incontinent subjects). The reason for not completing the urine sample will be 
documented. 
The laboratory evaluations will include, but not be limited to, the following: 
 Clinical Chemistry Serum Tests 
 
Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
 
Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH) 
 
HbA1c, glucose 
 
Albumin (ALB), total protein 
 
Prolactin 
 
Creatine kinase (CK)/creatine phosphokinase (CPK) 
 
Lipid panel 
o Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
Cholesterol/HDL ratio, Non-HDL cholesterol 
 Hematology Tests 
 
Complete blood count (CBC) including 
o White blood cell (WBC) count 
o Complete differential (relative and absolute) 
o Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
o Reticulocytes 
 Urinalysis 
 
Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
 
Urine pregnancy test for women with child-bearing potential. 
Note: Urinalysis requirement is not applicable to subjects who are unable to provide a urine 
sample (i.e., incontinent subjects). 
Blood samples will be taken during the study for routine safety tests (safety laboratory 
samples) (~4 total blood draws), as presented in Table 6–1 and detailed in the laboratory 
manual. 
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Table 6–1 
Safety Laboratory Evaluations 
Visit  
Tests* 
Baseline  
CHEM, CBC, UA , and urine pregnancy 
Weeks 4, 12, 28, and 52 (EOS/ET) 
CHEM, CBC, UA 
Weeks 4, 12, 20, 28, 36, 44, and 52 
(EOS/ET) 
Urine pregnancy 
Abbreviations: CBC=complete blood count; CHEM=serum chemistry; EOS/ET=end of study/early termination; 
UA=urinalysis 
* Urinalysis requirement not applicable to subjects who are unable to provide urine sample (i.e., incontinent 
subjects). 
 
Additional safety testing may be performed at the discretion of the Investigator or designate. 
6.2.8 
Clinically Significant Abnormalities 
Laboratory abnormalities judged by the Investigator to be clinically significant will be 
repeated as clinically appropriate. Abnormal laboratory test results that are considered to be 
clinically significant by the Investigator must be recorded as an AE. 
Further details on blood and urine sample collection are specified in the laboratory manual. 
6.2.9 
Suicidal Ideation and Behavior 
The Global Clinician Assessment of Suicidality (GCAS) will be used to assess the occurrence 
of treatment-emergent suicidal ideation and behavior. 
The GCAS is a clinician-rated, 5-point scale that is designed to rate the subject’s suicidality 
based on the report of the subject, the report of the study partner/caregiver, and the clinician’s 
global assessment. Ratings can be 0 (Absent), 1 (Feels life is not worth living), 2 (Wishes 
he/she were dead or any thoughts of possible death to self), 3 (Suicidal ideas or gesture), or 
4 (Attempt at suicide). The Investigator will record a subject rating, a partner/caregiver 
rating, and a clinician rating. For a rating of 3 or 4 based on the clinician’s assessment, the 
date of event will be recorded. At each visit, suicidality since the previous visit will be 
assessed.  
7 ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING 
7.1 
Adverse Events 
Adverse events occurring after the completion of procedures at the Week 12 visit in the 
double-blind Study ACP-103-032 will be recorded in the open-label Study ACP-103-033. 
Adverse events during ACP-103-033 will be recorded through the follow-up safety 
assessment (conducted by telephone call) approximately 30 days after the last dose of 
open-label study drug. All ongoing AEs from Study ACP-103-032 will be carried over and 
will be recorded from Baseline until resolution, or through the Week 52 (EOS/ET) visit. All 
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AEs must be either resolved or stable at the Week 52 (EOS/ET) visit. For those that are 
ongoing at the end of the study, the subject should be referred for appropriate treatment. 
7.2 
Definition of Adverse Events 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (CDER 2012). 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
An adverse reaction means any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. 
Suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the adverse event. 
AEs do not include the following: 
 Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to baseline and do not worsen during the study 
 Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if not present at 
baseline. 
 Overdose of either study drug or concomitant medication without any signs or 
symptoms unless the subject is hospitalized for observation 
 Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred) 
 Pregnancy will not be considered an AE, and if it occurs, it will be reported on a 
pregnancy form. 
When possible, clinical AEs should be described by diagnosis and not by symptoms (e.g., 
“cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. The description of each AE should use the 
following definitions: 
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Severity 
The severity of each AE will be graded on a 3-point scale and reported in detail as indicated 
on the eCRF: 
 Mild: awareness of sign or symptom but 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 
Relationship to Investigational Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related.” An event is considered related if there is “a reasonable possibility” that the 
event may have been caused by the product under investigation (i.e., there are facts, 
evidence, or arguments to suggest possible causation). 
Consider the following when assessing causality: 
 Temporal associations between the agent and the event, 
 Response to cessation (de-challenge) or re-challenge, 
 Compatibility with known class effect, 
 Known effects of concomitant medications, 
 Pre-existing risk factors, 
 A plausible mechanism, and 
 Concurrent illnesses. 
Duration 
The duration of the AE should be recorded using the following criteria: 
 Start: Date of the first episode of the AE or date of significant sustained worsening in 
severity 
 Stop: Date when AE either ceased permanently or changed in severity 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
 Single: Experienced once, without recurrence 
 Recurrent: More than one discrete episode with the same severity 
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Action Taken with Investigational Drug 
 Dose not changed: No change in study drug 
 Dose reduced: Dose of study drug reduced 
 Dose increased: Dose of study drug increased 
 Drug interrupted: Investigational drug temporarily stopped 
 Drug withdrawn: Investigational drug discontinued permanently 
Therapy 
 None: No new treatment instituted 
 Medication: New treatment initiated as a direct result of AE 
 Other: Other action required 
Outcome 
 Recovered/resolved: Recovered or resolved 
 Recovered/resolved with sequelae: Recovered or resolved with sequelae 
 Not recovered/not resolved: Not recovered or not resolved 
 Fatal: Death related to AE 
 Unknown: Unknown 
Seriousness 
 Not serious 
 Serious: Refer to definition in Section 7.3 
In the event that a subject is withdrawn from the study because of an AE, the subject should 
be followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established. 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE eCRF and the concomitant medication page. 
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Adverse events will be coded by data management using the most current version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator as described above. 
7.3 
Serious Adverse Events and Unexpected Adverse Events 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
 Is fatal, 
 Is immediately life threatening, 
 Results in disability or permanent damage, 
 Requires hospitalization, 
 Prolongs existing hospitalization, 
 Is a congenital anomaly or birth defect (in an offspring), or 
 Is medically significant. 
Definition of Life Threatening 
A life threatening event places the subject at immediate risk of death from the event as it 
occurred. This does not include an AE, which, had it occurred in a more severe form, might 
have caused death. 
Definition of Hospitalization 
Hospitalization is defined by ACADIA as a full admission to the hospital for diagnosis and 
treatment. This includes prolongation of an existing in-patient hospitalization.  
Examples of visits to a hospital facility that do not meet the serious criteria for hospitalization 
include: 
 Emergency room visits (that do not result in a full hospital admission) 
 Outpatient surgery 
 Preplanned or elective procedures (see Section 7.3.1) 
 Protocol procedures 
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 Social hospitalization, defined as inadequate family support or care at the subject's 
primary residence that results in the subject being admitted to the hospital 
Definition of Disability or Permanent Damage 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life 
threatening, or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
An SAE may also include any other event that the Investigator or Medical Monitor judges to 
be serious or that suggests a significant hazard, contraindication, side effect, or precaution. 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the applicable product information. 
7.3.1 
Elective Procedures and Surgeries 
For the purposes of this protocol, the following conventions will apply for SAE reporting of 
elective procedures and surgeries: 
A prescheduled elective procedure or a routinely scheduled treatment is not to be considered 
an SAE, even if the subject is hospitalized, provided the site stipulates that: 
 The condition requiring the prescheduled elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress between the subject’s 
consent to participate in the clinical trial and the time of the procedure or treatment, 
 The prescheduled elective procedure or routinely scheduled treatment is the sole 
reason for admission and intervention. 
An untoward medical event occurring during the prescheduled elective procedure or 
routinely scheduled treatment should be recorded as an AE or an SAE. Any concurrent 
medications should also be recorded on the eCRF. 
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7.4 
Other Reportable Information 
In addition, and for the purposes of monitoring, the following should be reported via the AE, 
SAE, and/or Pregnancy reporting forms, as appropriate: 
 Instances of overdose of study drug (where there are associated symptoms) (see 
Section 5.3 for definition of overdose); 
 Any occurrence of pregnancy (with or without AEs). 
Any subject who becomes pregnant during the study must be withdrawn from the study and 
will be followed through the first well-baby visit. Women of childbearing potential are 
permitted in this study. Women of non-childbearing potential are defined as those who have 
been postmenopausal for at least 12 months, who do not have a uterus, have bilateral tubal 
ligation, have undergone bilateral salpingectomy, and/or have both ovaries removed. 
7.5 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction 
assessed as unexpected by the Sponsor and that is judged by either the reporting Investigator 
or the Sponsor to have a reasonable causal relationship to a medical product. 
7.5.1 
Serious Adverse Event Reporting 
The reporting of SAEs by ACADIA to the Regulatory Authorities is a regulatory requirement. 
Each Regulatory Authority has established a timetable for reporting SAEs based upon 
established criteria. 
Serious AEs and Other Reportable Information (Sections 7.3 and 7.4) must be reported 
within 24 hours of discovery to ACADIA or its designee. The SAE (initial and/or follow-up), 
pregnancy, new diagnosis of cancer, or overdose of study drug must be reported within 
24 hours by completing the AE, SAE, and/or Pregnancy forms, as appropriate (refer to the 
Study Reference Manual for details). 
At a minimum, events identified by ACADIA to require expedited reporting as serious, 
unexpected, and possibly related to study drug must be brought to the attention of the 
responsible IRB/EC. For EU member states, ACADIA or its designee will provide reports of 
SUSARs directly to the ECs, as required by local legislation. In all other countries, it is the 
Investigator’s responsibility to provide these expedited reports to the responsible IRB/EC. It 
is also the Investigator’s responsibility to notify the responsible IRB/EC regarding any new 
and significant safety information. 
For this study, sites will complete the paper SAE, overdose, and/or pregnancy form (for 
initial and/or follow-up information), including available supporting documentation relevant 
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to the event and send (within 24 hours of discovery) to the contact numbers and/or email 
designated on the SAE form provided to the sites. 
Subjects will be followed until EOS/ET for any SAEs and/or other reportable information or 
until such events have resolved or the Investigator, in conjunction with ACADIA, deems 
them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the study follow-up period should be reported if in the judgment 
of the Investigator there is “a reasonable possibility” that the event may have been caused by 
the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.6 
Routine Safety Monitoring 
A Safety Management Team (SMT), internal to ACADIA, will regularly monitor all aspects 
of subject safety throughout this study. The SMT will be comprised of qualified 
representatives from Clinical Development, Drug Safety and Pharmacovigilance, and 
Regulatory Affairs, as well as other ad hoc representatives as appropriate. The SMT will meet 
regularly to review all SAEs and will examine aggregate non-serious AEs, clinical laboratory 
data, and other relevant safety data. 
7.7 
Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
withdrawn from the study and the pregnancy must be reported on the pregnancy form. Any 
female subject who becomes pregnant during the study will be followed through the first 
well-baby visit. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
(Section 7.3) should also be reported via the SAE forms provided and according to the 
directions in Section 7.6. 
7.8 
Emergency Treatment 
During and following a subject’s participation in the trial, the Investigator/institution should 
ensure that adequate medical care is provided to a subject for any AEs, including clinically 
significant laboratory values, related to the trial. The Investigator/institution should inform a 
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subject/study partner/caregiver when medical care is needed for intercurrent illness(es) of 
which the Investigator becomes aware. 
8 DATA RECORDING, RETENTION, AND MONITORING 
8.1 
Case Report Forms and Data Verification 
Subject data required by this protocol are to be recorded on eCRFs. The Investigator and 
his/her site personnel will be responsible for completing the eCRFs. The Investigator is 
responsible for the accuracy and reliability of all the information recorded on the eCRFs. All 
information requested on the eCRFs needs to be supplied, including subject identification 
date(s), assessment values, etc., and any omission or discrepancy will require explanation. All 
information on eCRFs must be traceable to source documentation at the site. 
The study monitors will be responsible for reviewing and verifying the data recorded on the 
eCRFs, utilizing the source documentation, and will query discrepant findings. The 
Investigator and site personnel will be responsible for answering all queries. The eCRFs will 
be submitted to ACADIA or its designee for quality assurance review and statistical analysis 
via an electronic data capture system. A copy of the final eCRFs will be retained by the 
Investigator, who must ensure that the copy is stored in a secure place. 
8.2 
Source Documentation 
All study specific medical information obtained at each study visit must be recorded in the 
subject’s record (source documentation) in real time as it is collected, and then entered into a 
validated electronic data capture clinical database by trained site personnel. The source 
documentation will consist of source notes captured by site personnel as well as laboratory 
reports, ECG reports, and electronic source data. 
8.3 
Availability and Retention of Records 
All documents required for the conduct of the study as specified in the International Council 
for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines will be maintained by the 
Investigator in an orderly manner and made available for monitoring and/or auditing by the 
Sponsor and regulatory agencies. 
The Investigator and institution must permit authorized representatives of ACADIA and/or 
designee (including monitors and auditors), the regulatory agency(s) (including inspectors), 
and the IRB/EC direct access to source documents (such as original medical records). Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
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Investigators are required to maintain all essential study documentation as per ICH-GCP. This 
includes, but is not limited to, copies of signed, dated and completed eCRFs, documentation 
of eCRF corrections, signed ICFs, subject-related source documentation, and adequate 
records for the receipt and disposition of all investigational drug. Investigators should 
maintain all essential study documentation, for a period of at least 2 years following the last 
approval of marketing application in an ICH region (United States, Europe, and Japan), or 
until at least 2 years after the drug investigational program is discontinued, unless a longer 
period is required by applicable law or regulation. Only ACADIA can notify an Investigator 
when any records may be discarded. Investigators should contact ACADIA before destroying 
any files. 
8.4 
Quality Control and Quality Assurance 
ACADIA and/or designee representatives and regulatory authority inspectors are responsible 
for contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the trial (e.g., eCRFs and other pertinent data) 
provided that subject confidentiality is respected. 
The ACADIA and/or designee monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH Guidance on GCP and ACADIA’s audit plans, a certain percentage 
of sites participating in this study will be audited. These audits may include a review of site 
facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of study-related 
records may occur in order to evaluate the trial conduct and compliance with the protocol, 
ICH Guidance on GCP, and applicable regulatory requirements. 
8.5 
Subject Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs or other documents submitted to ACADIA and/or designee, subjects must be 
identified by a Subject Identification Number only. Documents that are not for submission to 
ACADIA and/or designee (e.g., signed ICFs) should be kept in strict confidence by the 
Investigator in compliance with Federal regulations or other applicable laws or ICH 
Guidance on GCP. 
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ACADIA and/or designee representatives, regulatory authority inspectors and IRB/EC 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 
9 STATISTICAL PLAN 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by ACADIA prior to database lock. 
9.1 
General Statistical Methods 
For continuous variables the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean, standard deviation, minimum, maximum, and 
median. For categorical variables, summaries will include the number and percentage of 
subjects in each category, using the number of subjects with non-missing values as the 
denominator for the percentages (unless otherwise specified). 
No hypothesis testing is planned. Descriptive summaries of all safety and efficacy endpoints 
will be provided. All safety and efficacy measures will be summarized for the overall safety 
population. Summaries by treatment group according to the original treatment in Study 
ACP-103-032 (placebo, pimavanserin 20 mg, and pimavanserin 34 mg) will also be 
provided. All references to treatment group refer to the initial treatment group in Study 
ACP-103-032. 
For each continuous measure in safety and efficacy analyses, change from Baseline results 
will be presented in three ways: 
1. Using the Baseline from Study ACP-103-033 and reporting the changes across Study 
ACP-103-033 timepoints; 
2. Using the Baseline from Study ACP-103-032 and reporting the changes across the 
timepoints of both the double-blind Study ACP-103-032 and the open-label Study 
ACP-103-033; 
3. Based on the Baseline before the first dose of pimavanserin in either Study 
ACP-103-032 or ACP-103-033; changes will be reported across the timepoints using 
the Baseline from the double-blind Study ACP-103-032 for subjects receiving 
pimavanserin in the double-blind study (up to 64 weeks), and using the Baseline from 
Study ACP-103-033 for subjects receiving placebo in the double-blind study (up to 
52 weeks). 
All data summaries will be performed using SAS® V9.3 (SAS Institute, Inc., Cary, North 
Carolina) or higher. Validation and quality control of the tables, listings, and figures 
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containing the results of the data summaries will follow appropriate standard operating 
procedures (SOPs). 
9.2 
Determination of Sample Size 
The planned sample size for this study is not based on statistical power but will depend on 
the number of subjects who complete Study ACP-103-032 and who then transition into this 
open-label extension study. 
9.3 
Handling of Dropouts and Missing Data 
Handling of missing values will be described in detail in the SAP. For responder analyses, 
two sets of summaries will be provided, one based on observed cases and the other counting 
subjects with missing values as non-responders. 
9.4 
Subgroup Analyses 
Selected subgroup analyses will be specified in the SAP.  
9.5 
Study Subjects 
9.5.1 
Analysis Sets 
The Safety Analysis Set will include all subjects who received at least 1 dose of open-label 
study drug. The Safety Analysis Set will be used for all analyses. 
9.5.2 
Subject Accountability and Subject Disposition 
Study enrollment by center will be summarized. The number and percentage of subjects 
treated in the study will be presented, together with the number and percentage of subjects 
who completed the study and those who withdrew early. A breakdown of the corresponding 
reasons for early withdrawal from the study will be provided. 
9.5.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics 
and corresponding listings will be provided. 
9.6 
Efficacy Analyses 
Details regarding the scoring for each assessment scale will be provided in the SAP. 
Descriptive statistics for all efficacy endpoints will be tabulated by treatment group and 
timepoint. For selected continuous endpoints, figures displaying mean changes over time will 
also be provided. 
Responder analyses will be performed for the CMAI total score, selected individual NPI-C 
domain scores, and the mADCS-CGIC. Responder definitions for the CMAI total score and 
NPI-C domains will be provided in the SAP and will be the same as those used in 
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Study ACP-103-032. For the mADCS-CGIC, response is defined as moderate or marked 
improvement. Response rates will be summarized by treatment group and timepoint, using 
observed cases and also with missing values imputed as non-response. 
9.7 
Safety Analyses 
9.7.1 
Exposure to Study Drug 
For each subject, the duration of exposure to study drug will be calculated as the number of 
days from first dose date to last dose date inclusive. Descriptive statistics will be tabulated by 
treatment group. A categorical summary will also be provided using categories defined in the 
SAP. 
In addition, the maximum dose, final dose, and mean daily dose will be determined for each 
subject and summarized by treatment group. For maximum dose and final dose, a categorical 
summary by dose level (20 mg and 34 mg) will be provided. For mean daily dose, summary 
statistics will be tabulated by treatment group. 
9.7.2 
Adverse Events 
Adverse events will be classified into standard terminology using the MedDRA. All AEs will 
be listed and summarized by system organ class and preferred term. Summaries by maximum 
severity and by relationship to study drug will also be provided. Serious AEs, fatal AEs, and 
AEs leading to discontinuation will also be summarized. 
9.7.3 
Clinical Laboratory Values 
Descriptive statistics for clinical laboratory parameters, including changes from baseline, will 
be tabulated by treatment group and timepoint. 
The number and percentage of subjects with potentially clinically important post-baseline 
laboratory values will be summarized by treatment group and timepoint, as well as across all 
post-baseline timepoints, for selected parameters. The potentially clinically important criteria 
will be specified in the SAP. 
9.7.4 
Vital Signs and Body Weight 
Descriptive statistics for vital signs and body weight, including changes from baseline, will 
be tabulated by treatment group and timepoint. The number and percentage of subjects with 
changes from baseline (increases and decreases separately) in body weight of 7% or more 
will also be provided. 
9.7.5 
Electrocardiogram 
Descriptive statistics for ECG, including changes from baseline, will be tabulated by 
treatment group and timepoint. Additionally, categorical analyses will be conducted on the 
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incidence of subjects with prolonged QTc intervals and changes in QTc intervals in 
accordance with ICH guidelines and based on the FDA E14 Guidance Document. 
9.7.6 
Physical Examinations 
The results of the physical examinations at each visit (Baseline, Week 12, and Week 52 
[EOS/ET]) will be tabulated by treatment group and timepoint. 
9.7.7 
Suicidal Ideation and Behavior 
The number and percentage of subjects for each GCAS rating (0-4) based on clinician’s 
assessment will be tabulated by treatment group and visit. The number and percentage of 
subjects reporting any post-baseline GCAS score of 3 or 4 based on the clinician’s 
assessment will also be tabulated for each treatment group. 
10 REGULATORY COMPLIANCE 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH principles of GCP, and other applicable regulatory requirements. 
10.1 Institutional Review Board 
The Principal Investigator (PI) or designee will provide the IRB/EC with all requisite 
material, including a copy of the protocol, informed consent, and any subject information or 
advertising materials. The study will not be initiated until the IRB/EC provides written 
approval of the protocol and the informed consent and until approved documents have been 
obtained by the PI and copies received by the Sponsor. All amendments will be sent to the 
IRB/EC for information (minor amendment) or for submission (major amendment) before 
implementation. The PI will supply the IRB/EC and the Sponsor with appropriate reports on 
the progress of this study, including any necessary safety updates, in accordance with the 
applicable government regulations and in agreement with policy established by the Sponsor. 
10.2 Ethical Conduct of the Study 
The study will be performed in accordance with FDA GCP Regulations (US Code of Federal 
Regulations [CFR] 21 parts 50, 54, 56, and 312), and (ICH) GCP Guidelines (E6) and clinical 
safety data management (E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report (CSR) will be signed by an Investigator and/or Coordinating Investigator 
who will be designated prior to the writing of the CSR. 
10.3 Subject Information and Informed Consent 
Properly executed, written informed consent must be obtained from each subject or an 
appropriate person according to national and local regulations (e.g., the subject’s legally 
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authorized representative [LAR] with subject’s assent) prior to enrollment in the study. 
Additionally, written agreement must be obtained from the subject’s study partner/caregiver 
prior to any protocol evaluations, indicating that they understand the study, including their 
role as the study partner/caregiver and agree to participate in the study. This agreement is not 
a consent to become a study subject. 
The Informed Consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. Informed consent must be obtained 
from the subject’s LAR with the subject’s assent if the subject is deemed not competent to 
provide informed consent. A copy of the ICF planned for use will be reviewed by the 
Sponsor (or designee) for acceptability and must be submitted by the Investigator, together 
with the protocol, to the appropriate IRB/EC for review and approval prior to the start of the 
study at that investigational site. Consent forms must be in a language fully comprehensible 
to the prospective subject if the subject is signing or by the subject’s LAR if the LAR is 
signing. The Investigator must provide the Sponsor (or designee) with a copy of the IRB/EC 
letter approving the protocol and the ICF(s) before the study drug supplies will be shipped 
and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject. Any revision(s) must be submitted to the appropriate IRB/EC 
for review and approval in advance of use. 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject or LAR after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study. The subject or LAR must be given ample time to decide about 
study participation and opportunity to inquire about details of the study. The 
IRB/EC-approved consent form must be personally signed and dated by the subject or LAR 
with subject assent and by the person who conducted the informed-consent discussion. The 
Investigator or appropriate site personnel must document the details of obtaining informed 
consent in the subject’s study documents. The subject must be given a copy of the signed 
informed consent and the original maintained in the designated location at the site. 
10.4 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
10.5 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/EC in 
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accordance with local requirements and, if required, to the Regulatory Authority, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. No 
approval is required for notifications. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s participation in the trial, it is discovered that the subject 
did not meet all eligibility criteria, s/he will be discontinued, unless the discontinuation 
presents an unacceptable medical risk. The justification to allow the subject to continue in the 
trial will be made by the Sponsor, with medical input from the Investigator, and will be 
documented. If allowed to remain in the trial, this will be reported as a major protocol 
deviation and not a waiver. All follow-up safety assessments must be completed and 
documented as outlined in the protocol. The Investigator must report any protocol deviation 
to the Sponsor and, if required, to the IRB/EC in accordance with local regulations, within 
reasonable time. 
10.7 Termination of the Study 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may be any of, but not limited to, the following: 
 Occurrence of AEs unknown to date in respect of their nature, severity, and duration or 
the unexpected incidence of known AEs 
 Medical or ethical reasons affecting the continued performance of the study 
 Sponsor business reasons 
Regulatory Authorities also have the right to terminate the conduct of the study in their 
region for any reason. 
10.8 Publication 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
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11 DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of GCP and as described in 21 CFR parts 50, 54, 56, and 312 and according to applicable 
local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
or Consultant for review by you, your staff and the applicable Institutional Review 
Board/Ethics Committee. Your acceptance of this document constitutes agreement that you 
will not disclose the information contained herein to others without written authorization 
from the Sponsor. 
 
 
Principal Investigator: 
 
 
Signature 
 
Date 
 
 
 
 
 
 
Name (printed) 
 
 
 
 
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12 REFERENCES 
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Fox C, Crugel M, Maidment I, et al. Efficacy of memantine for agitation in Alzheimer’s 
dementia: a randomized double blind placebo controlled trial. PLoS ONE. 2012;7(5):e35185.
Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for 
clinical trials in Alzheimer’s disease. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S33-S39.
Gauthier S, Feldman H, Hecker J, et al. Efficacy of donepezil on behavioral symptoms in 
patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr. 2002;14(4):389-404.
Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with 
moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr 
Psychiatry. 2008;23(5):537-545.
Geiger Brown J, Wieroney M, Blair L, et al. Measuring subjective sleepiness at work in 
hospital nurses: validation of a modified delivery format of the Karolinska Sleepiness Scale. 
Sleep Breath. 2014;18(4):731-739.
Herrmann N, Lanctot KL. Pharmacologic management of neuropsychiatric symptoms of 
Alzheimer disease. Can J Psychiatry. 2007;52(10):630-646.
Janssen-Cilag Ltd. Risperdal® Tablets, Liquid and Quicklet [UK Summary of Product 
Characteristics]. High Wycombe, UK; June 2015. 
Johns MW. What is excessive daytime sleepiness? In: Fulke P, Vaughn S. Sleep deprivation:
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Koppel J, Greenwald BS. Optimal treatment of Alzheimer’s disease psychosis: challenges 
and solutions. Neuropsychiatr Dis Treat. 2014;10:2253-2262.
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Lopez OL, Becker JT, Sweet RA, et al. Psychiatric symptoms vary with the severity of 
dementia in probable Alzheimer’s disease. J Neuropsychiatry Clin Neurosci. 
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Lyketsos CG, Carrillo MC, Ryan JM, et al. Neuropsychiatric symptoms in Alzheimer’s 
disease. Alzheimers Dement. 2011;7(5):532-539. 
Lyketsos CG, Colenda CC, Beck C, et al. Position statement of the American Association for 
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Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of 
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McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
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McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database 
Syst Rev. 2006;19(2):CD003154. 
Mehta M, Manes FM, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpride in human volunteers. Psychopharmacology (Berl). 2004;176(3-4):331-
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Peretti CS, Danion JM, Kauffmann-Muller F, Grangé D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology (Berl). 1997;131(4):329-338. 
Peters ME, Schwartz S, Han D, Steinberg M, Tschanz, TZ, Lyketoss DG. Neuropsychiatric 
symptoms as predictors of progression to severe Alzheimer’s dementia and death: the Cache 
County Dementia Study. Am J Psychiatry. 2015,172(5):460-465. 
Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer 
disease: the CitAD randomized clinical trial. J Am Med Assoc. 2014;311(7):682-691. 
Rockwood K, Mitnitski A, Richard MK, Kurth M, Kesslak P, Abushakra S. Neuropsychiatric 
symptom clusters targeted for treatment at earlier versus later stages of dementia. Int J 
Geriatr Psychiatry. 2015;30(4):357-367. 
Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, 
on cognition and mood. Schiz Research. 2006;85(1-3):222-231. 
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Salzman C, Jeste DV, Meyer RE, et al. Elderly patients with dementia-related symptoms of 
severe agitation and aggression: consensus statement on treatment options, clinical trials 
methodology, and policy. J Clin Psychiatry. 2008;69(6):889-898. 
Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer’s Disease 
Cooperative Study – Clinical Global Impression of Change. The Alzheimer's Disease 
Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S22-S32. 
Soto M, Andrieu S, Nourhashemi F, et al. Medication development for agitation and 
aggression in Alzheimer disease: review and discussion of recent randomized clinical trial 
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Soto ME, Andrieu S, Villars H, et al. Improving care of older adults with dementia: 
description of 6299 hospitalizations over 11 years in a special acute care unit. J Am Med Dir 
Assoc. 2012;13(5):486 e1-e6. 
Steele C, Rovner B, Chase GA, Folstein M. Psychiatric symptoms and nursing home 
placement of patients with Alzheimer’s disease. Am J Psychiatry. 1990;147:1049-1051. 
Tariot PN, Raman R, Jakimovich L, et al. Divalproex sodium in nursing home residents with 
possible or probable Alzheimer Disease complicated by agitation: a randomized, controlled 
trial. Am J Geriatr Psychiatry. 2005;13(11):942-949. 
Tariot PN, Schneider LS, Cummings J, et al. Chronic divalproex sodium to attenuate 
agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry. 
2011;68(8):853-861. 
Teri L, Logsdon RG, Peskind E, et al. Treatment of agitation in AD: a randomized, placebo-
controlled clinical trial. Neurology. 2000;55(9):1271-1278. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) 
receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 
Wilcock GK, Ballard CG, Cooper JA, Loft H. Memantine for agitation/aggression and 
psychosis in moderately severe to severe Alzheimer's disease: a pooled analysis of 3 studies. 
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Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: correlates of 
feelings of burden. Gerontologist. 1980;20(6):649-655. 
 
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13 APPENDICES 
Appendix A 
Schedule of Events and Assessments .............................................................. 64
Appendix B 
Prohibited and Restricted Concomitant Medications ...................................... 66
Appendix C 
List of Prohibited CYP3A4 Inducers and Inhibitors ....................................... 69
Appendix D 
Cohen-Mansfield Agitation Inventory (CMAI)  SAMPLE ........................... 70 
Appendix E 
Zarit Burden Interview (ZBI)  SAMPLE ...................................................... 74 
Appendix F 
Neuropsychiatric Inventory – Clinician Rating Scale (NPI-C)  SAMPLE ... 78 
Appendix G 
Mini-Mental State Examination (MMSE)  SAMPLE ................................... 96 
Appendix H 
Modified Alzheimer’s Disease Cooperative Study – Clinical Global
Impression of Change (mADCS-CGIC)  SAMPLE ....................................100 
Appendix I 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living
Inventory (ADCS-ADL)  SAMPLE ............................................................107 
Appendix J
Karolinska Sleepiness Scale (KSS)  SAMPLE ...........................................116 
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APPENDIX A 
SCHEDULE OF EVENTS AND ASSESSMENTS 
Visit Number 
Treatment Period 
 
Follow-
Up 
Baselineb 
1 
2 
3 
4 
5 
6 
7 
8 
9 
(EOS/ET) 
10 
Unscheduled 
11 
Visit Weeka 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
20 
Week 
28 
Week 
36 
Week 
44 
Week  
52 
Week 56 
Allowable visit window (# days) 
 
3 
3 
3 
3 
7 
7 
7 
7 
+7 
 
+7 
Informed consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECGc 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Clinical laboratory tests 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Pregnancy testd 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
CMAI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
ZBI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NPI-C (all domains) 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
NPI-C (agitation and aggression domains only) 
 
X 
X 
X 
 
 
 
 
 
 
 
 
MMSE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
KSS 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
mADCS-CGIC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
ADCS-ADL  
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Assessment of concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of AEse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GCAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drugf 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Abbreviations and footnotes on next page. 
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Abbreviations: ADCS-ADL=Alzheimer’s Disease Cooperative Study–Activities of Daily Living; AE(s)=adverse event(s); CMAI=Cohen-Mansfield Agitation 
Inventory; ECG=electrocardiogram; EOS/ET=end-of-study/early termination; GCAS= Global Clinician Assessment of Suicidality; KSS=Karolinska 
Sleepiness Scale; mADCS-CGIC=modified Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change; MMSE=Mini-Mental State 
Examination; NPI-C=Neuropsychiatric Inventory-Clinician rating scale; ZBI=Zarit Burden Interview 
a 
Study visits are designated by weeks and have a ±3-day window (Visits 2 through 5), or a ±7-day window (Visit 6 through 9), or a +7-day window (Visits 10 
and 11) calculated from the Baseline Visit. 
b 
Study ACP-103-033 subjects must be consented prior to the final procedures being performed for Study APC-103-032 at Week 12. Procedures from the 
Week 12 visit of Study ACP-103-032 will be carried over as baseline information, if applicable. 
c 
A single 12-lead ECG can be performed any time before blood sampling or at least 30 minutes after blood sampling during clinic visits. 
d 
A urine pregnancy test should be performed for female study subjects of childbearing potential. 
e 
Any untoward medical occurrence that occurs after the completion of procedures at the Week 12 visit in double-blind Study ACP 103-032 should be 
recorded as an AE, even if dosing for ACP-103-033 has not begun. 
f 
Study drug will be dispensed to the subject at either scheduled or unscheduled visits. 
g 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject and their study partner/caregiver will be provided instructions to 
take the first dose of study drug on the following day. 
h 
To be completed at unscheduled visits where there is a dose change. 
 
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APPENDIX B 
PROHIBITED AND RESTRICTED CONCOMITANT MEDICATIONS 
The following is an outline of the prohibitions and restrictions on concomitant 
medications. Any questions regarding prohibited and restricted concomitant medications 
should be discussed with the Medical Monitor or appropriate designee. 
Subjects who take prohibited concomitant medications during the trial will be discontinued, 
unless the discontinuation presents an unacceptable medical risk. The justification to allow 
the subject to continue in the trial will be made by the Sponsor with medical input from the 
Investigator, and will be documented. If allowed to remain in the trial, this will be reported as 
a major protocol deviation and not a waiver. 
1. Antipsychotics:  
○ All antipsychotics are prohibited and should be discontinued as appropriate 
2 weeks or at least 5 half-lives (whichever is longer) prior to Baseline. 
2. Serotonin antagonists: 
○ Serotonin antagonists are prohibited and must have been discontinued at least 
3 weeks prior to Baseline. This includes, but is not limited to: mianserin, 
nefazodone, cyproheptadine, and fluvoxamine. 
○ Trazodone is prohibited as a serotonin antagonist and also due to possible QT 
prolongation. 
3. Anticholinergic medications: 
○ Centrally acting anticholinergic medications are prohibited. These include, but are 
not limited to, diphenhydramine, benztropine, biperiden, and trihexyphenidyl. 
○ Peripherally acting anticholinergic agents, such as tolterodine or oxybutynin, are 
allowed. 
4. Antidepressants: 
○ Use of antidepressant medications is restricted. The dose of these medications 
must be expected to remain unchanged until the subject’s final visit. 
○ Trazodone is prohibited as an antidepressant and also due to possible QT 
prolongation. 
○ See also the restrictions on antidepressants that can prolong the QT interval in #6 
below. These antidepressants include citalopram, escitalopram, clomipramine, 
desipramine, imipramine, mirtazapine, and nortriptyline 
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5. Anxiolytics and sedative medications: 
○ Use of anxiolytic medications (including benzodiazepine) is restricted. The dose 
of these medications should be expected to remain unchanged until the subject's 
final visit.  
○ Exception: lorazepam (a benzodiazepine) may be used as a rescue medication for 
the management of agitation and/or aggression per Section 5.6.3. If lorazepam is 
not available, another intermediate-acting benzodiazepine may be used in the 
same way lorazepam may be used at doses equivalent to lorazepam doses. 
○ Use of sedative insomnia aids is permitted PRN with restrictions as noted in the 
list of prohibited and restricted medications. 
6. Medications that can prolong QT interval  
Medications that can prolong QT interval are prohibited or restricted as outlined below. These 
include, but are not limited to the following: 
Prohibited for the duration of the study: 
○ Antiarrhythmic drugs including: dronedarone, quinidine, procainamide, 
disopyramide, ajmaline, flecainide, propafenone, amiodarone, sotalol, d-sotalol, 
bretylium, ibutilide, dofetilide, amakalant, and semantilide 
○ Antimicrobial and antimalarial drugs; levofloxacin, moxifloxacin, erythromycin, 
clarithromycin, and pentamidine 
○ Methadone and cocaine 
 Restricted Medications 
○ Use of ciprofloxacin and azithromycin is prohibited. However, use of these drugs 
during the course of the study to treat a bacterial infection (e.g., urinary tract 
infection, respiratory infection) may be permitted at the discretion of the PI. 
○ Use of acetylcholinesterase inhibitors is allowed. The dose of these 
acetylcholinesterase inhibitors should remain at a stable dose throughout the study 
if possible. 
○ Citalopram and escitalopram are restricted to a maximum dose of 20 mg a day.  
○ The medications listed are ONLY allowed if:  
 
the subject has a baseline ECG with a QTcF <425 ms OR  
 
the subject has a QTcF <450 ms at Baseline AND QRS duration ≥120 ms 
(e.g., subjects with right bundle branch block [RBBB] or left bundle branch 
block [LBBB], an intraventricular conduction disturbance [IVCD], or 
ventricular pacing)  
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Antimicrobials, antifungals, and 
antimalarials 
Antidepressants 
Others 
 artenimol/piperaquine 
 bedaquiline 
 gemifloxacin 
 norfloxacin 
 ofloxacin 
 quinine 
 roxithromycin 
 clomipramine 
 desipramine 
 imipramine 
 mirtazapine 
 nortriptyline 
 felbamate 
 
 
○ The medications listed above are not allowed if a subject has a QTcF ≥425 ms 
and a QRS duration <120 ms at baseline.  
 
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APPENDIX C 
LIST OF PROHIBITED CYP3A4 INDUCERS AND INHIBITORS 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP3A4 inhibitors and inducers. Any questions should be discussed 
with the Medical Monitor or appropriate designee.  
The metabolism of pimavanserin is affected by strong cytochrome P450 (CYP) 3A4 enzyme 
(CYP3A4) inhibitors, resulting in an increase in maximum plasma concentration (Cmax) and 
area under the plasma concentration-time curve (AUC) of approximately 3-fold. Strong 
inhibitors and inducers of CYP3A4 are to be stopped 1 week prior to the administration of 
study drug and are prohibited throughout the study. Moderate inhibitors and inducers of 
CYP3A4 are allowed but should be used with caution. 
STRONG 
INDUCERS 
Avasimibe 
Carbamazepine (Tegretol®) 
Phenobarbital (Luminal®, 
Solfoton®) 
Phenytoin (Dilantin®)  
Rifampin (Rifadin®, Rifadin® 
IV, Rimactane®) 
St. John's Wort 
MODERATE 
INDUCERS 
Bosentan (Tracleer®) 
Efavirenz (Sustiva®) 
Etravirine (Intelence®) 
Modafinil (Provigil®) 
Nafcillin (Unipen, Nallpen®) 
STRONG 
INHIBITORS 
Boceprevir (Victrelis®) 
Clarithromycin (Biaxin®)  
Cobicistat (part of Stribild®) 
Conivaptan (Vaprisol®) 
Fluvoxamine (Luvox®) 
Grapefruit juicea  
Indinavir (Crixivan®)  
Itraconazole (Sporanox®)  
Ketoconazole (Nizoral®)  
Lopinavir and Ritonavir 
(Kaletra®) 
Mibefradil (Posicor®) 
Nefazodone (Serzone®)  
Nelfinavir (Viracept®)  
Posaconazole (Noxafil®) 
Quinupristin (Synercid®) 
Ritonavir (Norvir®, part of 
Viekira Pak™)  
Saquinavir (Invirase®)  
Telaprevir (Incivek®) 
Telithromycin (Ketek®)  
Voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
Amprenavir (Agenerase®) 
Aprepitant (Emend®) 
Atazanavir (Reyataz®) 
Ciprofloxacin (Cipro®) 
Darunavir/ritonavir 
(Prezista®/Ritonavir) 
Diltiazem 
Erythromycin  
Fluconazole (Diflucan®) 
Fosamprenavir (Lexiva®) 
Grapefruit juicea 
Imatinib (Gleevec®) 
Verapamil (Calan®) 
a  
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 
 
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APPENDIX D 
COHEN-MANSFIELD AGITATION INVENTORY (CMAI)  SAMPLE 
Source: Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in a nursing 
home. Journal of Gerontology Medical Sciences. 1989;44(3):M77-M84. 
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APPENDIX E 
ZARIT BURDEN INTERVIEW (ZBI)  SAMPLE 
Source: Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: correlates 
of feelings of burden. Gerontologist. 1980;20(6):649-655. 
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APPENDIX F 
NEUROPSYCHIATRIC INVENTORY – CLINICIAN RATING SCALE 
(NPI-C)  SAMPLE 
Source: Used with permission from ©JL Cummings, 1994; all rights reserved. Electronic 
programming and presentation design copyright of MedAvante 2016. 
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APPENDIX G 
MINI-MENTAL STATE EXAMINATION (MMSE)  SAMPLE 
Source: Used with permission from the Publisher, Psychological Assessment Resources, Inc., 
 from the Mini-Mental State Examination 
by Marshal Folstein and Susan Folstein, Copyright 1975, 1998, 2001 by Mini Mental LLC, 
Inc. Published 2001 by Psychological Assessment Resources, Inc. 
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APPENDIX H 
MODIFIED ALZHEIMER’S DISEASE COOPERATIVE STUDY – 
CLINICAL GLOBAL IMPRESSION OF CHANGE (mADCS-CGIC)  SAMPLE 
Source: Used with permission from the NIA Alzheimer’s Disease Cooperative Study 
 
Reference: Schneider L, Olin J, Doody R, et al., and the ADCS. Validity and Reliability of 
the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. 
Alzheimer’s Disease and Associated Disorders, 1997. Vol 11(2): S22-S32. 
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APPENDIX I 
ALZHEIMER’S DISEASE COOPERATIVE STUDY-ACTIVITIES OF 
DAILY LIVING INVENTORY (ADCS-ADL)  SAMPLE 
Source: Used with permission from the NIA Alzheimer’s Disease Cooperative Study 
Galasko, D., Bennett, D., Sano, M., Ernesto, E., Thomas, R., Grundman, 
M., and Ferris, S. Alzheimers Disease and Associated Disorders 1997; 11:S33-S39. 
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APPENDIX J 
KAROLINSKA SLEEPINESS SCALE (KSS)  SAMPLE 
References:  
Åkerstedt T, Gillberg M. Subjective and Objective Sleepiness in the Active Individual. 
International Journal of Neuroscience. 1990; 52:1-2, 29-37. 
Geiger Brown J, Wieroney M, Blair L, et al. Measuring subjective sleepiness at work in 
hospital nurses: validation of a modified delivery format of the Karolinska Sleepiness Scale. 
Sleep Breath. 2014;18(4):731-9. 
Johns MW. What is excessive daytime sleepiness? In: Fulke P, Vaughn S. Sleep deprivation: 
causes, effects and treatment. New York, NY;Nova Science. 2009;59-94. 
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