A Double-Blind, Placebo-Controlled Study to Examine the Safety and Efficacy of Pimavanserin for the Treatment of Agitation and Aggression in Alzheimer's Disease
Phase: PHASE2
Conditions: Agitation and Aggression in Alzheimer's Disease
Sponsor: ACADIA Pharmaceuticals Inc.

Official Title: A Double-Blind, Placebo-Controlled Study to Examine the Safety and 
Efficacy of Pimavanserin for the Treatment of Agitation and Aggression in 
Alzheimer’s Disease 
NCT Number: NCT02992132 
Date of IRB Approval: 28 December 2017 

 
 
 
ACADIA Pharmaceuticals Inc. 
 
 
Clinical Study Protocol 
Amendment 3 
A Double-Blind, Placebo-Controlled Study to Examine the Safety and 
Efficacy of Pimavanserin for the Treatment of Agitation and Aggression 
in Alzheimer’s Disease  
Protocol No. ACP-103-032 
EudraCT Number: 2016-001127-32 
 
Original Protocol Date: 18 April 2016 
Amendment 01 Protocol Date: 12 August 2016 
Amendment 2 Protocol Date: 18 July 2017 
Amendment 3 Protocol Date: 20 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. 
 
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Study: ACP-103-032 
Protocol Amendment 3 
SPONSOR SIGNATURE PAGE 
Final Version: 1.0 
Date: 20 November 2017 
Title: A Double-Blind, Placebo-Controlled Study to Exat ine the Safety and Efficacy of 
Pimavanserin for the Treatment of Agitation and Aggress·on in Alzheimer's Disease 
ACADIA Chief Medical Officer: 
ACADIA Team Lead: 
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Page 2of130 

 
  
 
 
SPONSOR CONTACTS 
 
ACADIA Medical Contact: 
 
 
ACADIA Clinical Contact: 
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PROTOCOL SYNOPSIS 
Protocol Number ACP-103-032 
Title 
A Double-Blind, Placebo-Controlled Study to Examine the Safety and 
Efficacy of Pimavanserin for the Treatment of Agitation and Aggression 
in Alzheimer’s Disease 
Phase of 
Development 
2 
Name of Drug 
Pimavanserin 
Indication 
Agitation and Aggression in Alzheimer’s Disease (AD) 
Sponsor 
ACADIA Pharmaceuticals Inc. 
 
 
Sponsor Contact 
 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
 
Test Product, 
Dose, and Mode 
of 
Administration: 
Pimavanserin 34 mg (provided as 2×17 mg tablets), pimavanserin 20 mg 
(provided as 2×10 mg tablets), or matching placebo (2×placebo tablets) 
will be administered orally once daily. 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.  
Objectives 
The purpose of this study is to evaluate the efficacy and safety of 
pimavanserin at doses of 34 mg and 20 mg, compared with placebo in 
the treatment of agitation and aggression in subjects with probable AD. 
Primary Objective:  
 To evaluate the efficacy of pimavanserin compared with placebo 
in the treatment of agitation and aggression after 12 weeks. 
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Secondary Objective:  
 To evaluate the efficacy of pimavanserin compared with placebo on 
caregiver burden 
Exploratory Objectives: 
 To evaluate the efficacy of pimavanserin compared with placebo for 
the following: 
 Clinician’s global assessment of treatment benefit 
 Other neuropsychiatric symptoms  
 Functional status  
 Sleep and daytime wakefulness 
 Cognition 
 Need for rescue medication 
 To evaluate the safety and tolerability of pimavanserin  
 To evaluate the plasma concentrations of pimavanserin and the major 
metabolite AC-279   
Methodology 
This study will be conducted as a Phase 2, 12-week, randomized, 
double-blind, placebo-controlled, multicenter, outpatient study designed 
to assess the safety and efficacy of pimavanserin at doses of 34 mg and 
20 mg versus placebo in subjects with a diagnosis of probable AD 
according to the National Institute on Aging-Alzheimer’s Association 
(NIA-AA) guidelines who have clinically significant 
agitation/aggression and who meet the following criteria: 
 Mini-Mental State Examination (MMSE) score of 5 to 26 
(inclusive) at the Screening Visit  
 Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C) 
combined agitation and aggression domain score of ≥14 at both 
the Screening and Baseline visits  
Screening Period 
The screening period will be at least 2 to 4 weeks in duration. Subjects 
will have psychosocial therapy for the duration of the screening period 
prior to randomization. Subjects on antipsychotic medication at the 
beginning of the screening period will discontinue that medication 
(wash-out of at least 5 half-lives) during the screening period. Subjects 
who screen fail will be allowed to rescreen with agreement of the 
Medical Monitor. 
Double-Blind Treatment Period (Baseline through Week 12) 
The Baseline visit (Day 1) may occur as soon as all screening procedures 
are completed and subject eligibility has been confirmed. Subjects will 
be randomized in a 1:1:1 ratio to 1 of 3 treatment groups (pimavanserin 
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34 mg, pimavanserin 20 mg, or placebo), and stratified according to 
geographic region (North America, Europe, or Rest of World). Clinic 
visits occurring after Baseline will be conducted at Weeks 2, 4, 8, and 
12, or upon early termination (ET) from the study. It is recommended 
that the subject take the study drug at approximately the same time each 
day. 
All concomitant medications, including cholinesterase inhibitors, 
memantine, antidepressants, and other permitted medications, should be 
expected to remain at a stable dose throughout the study. 
Subjects who successfully complete the 12-week treatment period will 
be eligible to enroll in an open-label safety extension study if they 
qualify. For subjects who discontinue prematurely from the study or who 
do not enroll in the open-label extension study, a follow-up safety 
assessment will be conducted by telephone call approximately 30 days 
after the last dose of study drug.  
Number of Study 
Sites 
Approximately 70 study sites will participate in this study. 
Number of 
Subjects Planned 
The original planned sample size was approximately 432. For business 
reasons, not related to safety, the enrollment (randomization) of new 
subjects into the study was stopped after 111 subjects were randomized. 
The last subject was randomized into the study on November 2, 2017. 
Study Population Subjects who meet all of the inclusion criteria and none of the exclusion 
criteria are eligible to enter the treatment phase. 
Protocol waivers for eligibility will not be granted by the Sponsor under 
any circumstances.  
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. Male or female, 50 years of age or older  
3. Has a diagnosis of probable AD according to NIA-AA guidelines 
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4. Meets criteria for agitation according to the International 
Psychogeriatric Association (IPA) guidelines (see Appendix B)  
5. Has an MRI or CT scan (brain imaging) taken during or subsequent 
to diagnosis of probable AD, or during the screening period (prior to 
Baseline)  
6. Has a Mini-Mental State Examination (MMSE) score of 5 to 26 
(inclusive) at Screening 
7. Has agitation/aggression defined as a Neuropsychiatric Inventory-
Clinician rating scale (NPI-C) combined agitation and aggression 
domain score of ≥14 at both the Screening and Baseline visits  
8. Lives at home or in an assisted living or care facility (but has the 
capacity to visit the clinic as an outpatient). Subjects must have been 
at their current location for at least 3 weeks prior to Screening and 
plan to remain at the same location for the duration of the trial. 
9. 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 must: 
 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 these areas of the subject’s behavioral 
and functional status.  
10. 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  
11. 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 
12. Both subject and study partner/caregiver are willing and able to 
participate in all scheduled evaluations and complete all required 
tests 
13. If taking antidepressants, has been on a stable dose for at least 
4 weeks prior to the Baseline visit and should be expected to remain 
on a stable dose throughout the trial  
14. If taking cholinesterase inhibitors and/or memantine, has been on a 
stable dose for at least 12 weeks prior to the Baseline visit and should 
be expected to remain on a stable dose throughout the trial 
15. 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, 
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intrauterine device [IUD; diaphragm], injectable, transdermal or 
implantable contraception) or abstinence, for at least 1 month prior to 
randomization, during the study, and 1 month following completion 
of the study. 
Females of childbearing potential must have a negative serum human 
chorionic gonadotropin (hCG) pregnancy test at Screening and a 
negative urine hCG pregnancy test at Baseline 
Exclusion Criteria: 
1. The agitation/aggression is attributable to concomitant medications, 
environmental conditions, substance abuse, or active medical or 
psychiatric condition  
2. Has a current major depressive disorder episode (within 3 months) 
according to the Diagnostic and Statistical Manual of Mental 
Disorders - Fifth Edition (DSM-5) criteria  
3. Treatment with an antipsychotic medication within 2 weeks of 
Baseline visit or 5 half-lives, whichever is longer  
Investigators should not withdraw a subject’s prohibited medication 
for the purpose of enrolling them into the study unless 
discontinuation of the medication is deemed to be clinically 
appropriate (e.g., symptoms are not well-controlled or the subject 
cannot tolerate the current medication).  
4. Has brain abnormalities seen on an MRI or CT scan (brain imaging) 
taken during or subsequent to diagnosis of probable AD, that can be 
attributed to diseases or processes other than AD, including but not 
limited to: 
 
multiple lacunar infarcts or evidence of a single prior infarct 
>1 cm3; 
 
intracranial mass lesion (including but not limited to meningioma 
[>1 cm3 with evidence of peritumoral edema]); or 
 
glioma, vascular malformation, or macrohemorrhage 
5. Subject or study partner/caregiver has a medical condition (e.g., 
hearing, vision impairments) that would impair the ability to perform 
the study assessments. 
6. Subject requires treatment with a medication prohibited by the 
protocol (see Section 5.7, Appendix C, and Appendix D) 
7. Subject has had a myocardial infarction within the last 6 months 
prior to Screening 
8. Subject has a known history or symptoms of long QT syndrome  
9. Subject has a QRS interval <120 ms and whose Fridericia’s corrected 
QT interval (QTcF) is >460 ms at Screening or at Baseline OR 
subject has a QRS interval ≥120 ms and QTcF is >480 ms at 
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Screening or at Baseline 
10. Has clinically significant laboratory abnormalities that, in the 
judgment of the Investigator or Medical Monitor, would jeopardize 
the safe participation of the subject in the study  
11. Has a history of a significant psychotic disorder prior to or 
concomitant with the diagnosis of probable AD including, but not 
limited to, schizophrenia or bipolar disorder 
12. Subject is 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  
13. Has participated in or is participating in a clinical trial of any 
investigational drug, device, or intervention, and within 4 weeks (or 
5 half-lives, whichever is longer) of the Baseline visit 
14. Subject with sensitivity to pimavanserin or its excipients 
15. Subject has previously participated in a clinical study with 
pimavanserin 
16. Subject is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study 
17. 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)  
18. Has a body mass index (BMI) of <18.5 
19. Has an abnormal vitamin B12 result at screening or within the prior 
12 months prior to Visit 1 (Screening) that has not been successfully 
treated 
20. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 
or 4 based on Investigator’s assessment of behavior within the last 
3 months at Screening or since-last-visit at Baseline 
Duration of 
Treatment  
The duration of participation for individual subjects will be up to 
approximately 20 weeks. Each subject will participate in a 2- to 4-week 
screening period, a 12-week treatment period, and a 30-day safety 
follow-up (telephone call) for those subjects who discontinue 
prematurely from the study or who do not enroll in the open-label 
extension study. The end of the clinical trial will be when the last subject 
completes the last scheduled assessment (i.e., 30-day follow-up or 
enrolled in the extension study). 
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Subject 
Assignment 
Eligible subjects will be randomized to receive 1 of 3 treatments in a 
1:1:1 ratio within each geographic region (North America, Europe, or 
Rest of World): 
 Pimavanserin 34 mg 
 Pimavanserin 20 mg 
 Placebo 
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. 
Sample Size 
Calculations 
The original planned sample size was approximately 432. For business 
reasons, not related to safety, the enrollment (randomization) of new 
subjects into the study was stopped after 111 subjects were randomized. 
The last subject was randomized into the study on November 2, 2017. 
Thus, this study is not powered to definitively evaluate efficacy 
measures and only descriptive summaries will be provided. 
Efficacy 
Assessments and 
Endpoints 
Primary Endpoint: 
 Change from Baseline to Week 12 in CMAI total score 
Secondary Endpoint: 
 Change from Baseline to Week 12 in the ZBI total score 
Exploratory Endpoints: 
 Modified Alzheimer’s Disease Cooperative Study – Clinical 
Global Impression of Change (mADCS-CGIC) agitation score  
 Change from Baseline in NPI-C combined agitation and 
aggression domain scores  
 Change from Baseline in NPI-C individual agitation and 
aggression domain scores 
 Change from Baseline to Week 12 in Alzheimer’s disease 
Cooperative Study – Activities of Daily Living Inventory 
(ADCS-ADL) score 
 Change from Baseline to Week 12 in NPI-C total score 
 Change from Baseline to Week 12 in NPI-C sleep disorders 
domain score 
 Change from Baseline to Week 12 in NPI-C combined delusions 
and hallucinations domain scores 
 Change from Baseline to Week 12 in NPI-C combined dysphoria 
and apathy/indifference domain scores  
 Change from Baseline to Week 12 in individual NPI-C domain 
scores (other than agitation, aggression, and sleep disorders) 
 Change from Baseline in CMAI subscale scores  
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 Change from Baseline in Karolinska Sleepiness Scale (KSS) 
score 
 Change from Baseline in MMSE score 
 Proportion of subjects taking any rescue medication during the 
12-week treatment period  
Safety and 
Tolerability 
Assessments and 
Endpoints 
Safety will be evaluated descriptively on the basis of the following 
assessments: 
 Incidence and severity of treatment-emergent AEs (TEAEs), 
serious AEs (SAEs), and withdrawals due to adverse events 
(AEs) 
 Global Clinician Assessment of Suicidality (GCAS) 
 Clinically important changes in the following safety assessments: 
vital sign measurements, weight, clinical laboratory assessments, 
physical examinations, and electrocardiograms (ECGs) 
An independent Safety Monitoring Committee (SMC) will review safety 
information per the SMC charter. 
Pharmacokinetic 
Assessments and 
Endpoints 
Blood samples of pimavanserin will be collected at Baseline (pre-dose), 
Weeks 2, 4, and 12 (end of study [EOS]/ET). (Note: If collection at 
Week 2 does not occur, then collection should be attempted at Week 8.) 
When possible, blood samples of pimavanserin will be collected from 
subjects who experience an SAE or an AE leading to discontinuation. 
For all PK samples (scheduled and unscheduled), the dates and times of 
administration of the last 3 doses of study drug should be recorded. For 
samples collected from subjects who experience an SAE or an AE 
leading to discontinuation, the date and time of the last dose prior to the 
SAE or AE should also be recorded. 
Plasma concentration data will not be analyzed until the official 
unblinding of the clinical database at the end of the study. 
Pharmacokinetic Endpoint: 
 Plasma concentration of pimavanserin and AC-279 
Statistical 
Methods 
The Full Analysis Set includes all randomized subjects who received at 
least 1 dose of blinded study drug and who have both a baseline value 
and at least 1 post-baseline value for the CMAI total score. The Full 
Analysis Set will be used for the summary of all efficacy endpoints.  
The Per-protocol (PP) Analysis Set will be defined prior to unblinding 
the study for the final summaries. Subjects will be summarized based on 
their randomized treatment assignment.  
Safety summaries will be conducted using the Safety Analysis Set, 
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which is defined as all subjects who received at least 1 dose of blinded 
study drug. 
Subgroup Analysis 
Selected subgroup analyses will be specified in the statistical analysis 
plan (SAP). 
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 
outcome, the number and percentage of subjects in each category will be 
reported. 
Missing Data 
Handling of missing values will be described in detail in the SAP.  
Efficacy Analyses 
All efficacy endpoints will be summarized by treatment group using 
descriptive statistics. No hypothesis testing is planned. 
The CMAI total score will be summarized using mixed model repeated 
measures (MMRM). The dependent variable will be the change from 
baseline in the CMAI total score. The independent variables in the model 
will include the following: treatment group (pimavanserin 34 mg, 
pimavanserin 20 mg, or placebo), visit (Weeks 2, 4, 8, and 12), the 
treatment-by-visit interaction, the baseline CMAI total score, the 
Baseline-by-visit interaction, and geographic region (North America, 
Europe, or Rest of World).  
The mADCS-CGIC agitation score at each timepoint will be summarized 
using an MMRM model with effects for treatment group (pimavanserin 
34 mg, pimavanserin 20 mg, or placebo), visit (Weeks 2, 4, 8, and 12), 
the treatment-by-visit interaction, and geographic region (North 
America, Europe, or Rest of World). There is no baseline value to 
include in the model. In addition, the proportion of subjects with 
moderate or marked improvement on the mADCS-CGIC will be 
summarized by treatment group at each timepoint using observed cases 
and also with missing values imputed as non-response. 
The change from baseline to each post-baseline timepoint in the ZBI 
total score, the NPI-C combined agitation and aggression domain scores, 
NPI-C individual agitation and aggression domain scores, CMAI 
subscale scores, KSS, and MMSE will be summarized using an MMRM 
model similar to that described above for the primary endpoint, except 
that the baseline value of the endpoint being summarized will be 
included in the model instead of the baseline CMAI total score. Also, the 
MMSE is not measured at Week 2. 
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The change from baseline to Week 12 in the Alzheimer’s Disease 
Cooperative Study – Activities of Daily Living (ADCS-ADL) and NPI-C 
total score and individual domain scores (except the agitation and 
aggression domains) will be summarized using an analysis of covariance 
(ANCOVA) model with effects for treatment group (pimavanserin 
34 mg, pimavanserin 20 mg, or placebo), baseline value of the endpoint 
being summarized, and geographic region (North America, Europe, or 
Rest of World). 
The proportion of subjects taking any rescue medication during the 
treatment period will be summarized by treatment groups. 
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). 
Treatment-emergent AEs, fatal TEAEs, TEAEs leading to 
discontinuation, TEAEs related to study drug, TEAEs by maximum 
severity, serious TEAEs, and serious TEAEs related to study drug will 
all be summarized.  
Descriptive statistics for ECG, vital signs, and clinical laboratory 
parameters, including changes from baseline, will be tabulated by 
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. 
Pharmacokinetic Analyses  
Plasma concentration data for pimavanserin and its active metabolite 
(AC-279) will be listed and summarized using descriptive statistics. 
Date: 
20 November 2017 
 
 
 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE .............................................................................................. 2 
SPONSOR CONTACTS ........................................................................................................... 3 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
TABLE OF CONTENTS......................................................................................................... 14 
LIST OF TABLES ................................................................................................................... 17 
LIST OF FIGURES ................................................................................................................. 17 
LIST OF APPENDICES .......................................................................................................... 18 
ABBREVIATIONS AND ACRONYMS ................................................................................. 19 
1 BACKGROUND INFORMATION .................................................................................. 21 
1.1 
Investigational Drug ................................................................................................. 23 
1.2 
Previous Clinical Experience ................................................................................... 23 
1.3 
Study Rationale ........................................................................................................ 24 
2 OBJECTIVES .................................................................................................................... 25 
2.1 
Primary Objective and Endpoint .............................................................................. 25 
2.1.1 
Primary Objective ....................................................................................... 25 
2.1.2 
Primary Endpoint ........................................................................................ 25 
2.2 
Secondary Objective and Endpoint .......................................................................... 25 
2.2.1 
Secondary Objective ................................................................................... 25 
2.2.2 
Secondary Endpoint .................................................................................... 25 
2.3 
Exploratory Objectives and Endpoints ..................................................................... 25 
2.3.1 
Exploratory Objectives ............................................................................... 25 
2.3.2 
Exploratory Endpoints ................................................................................ 26 
3 STUDY DESIGN .............................................................................................................. 27 
3.1 
Overall Study Design ............................................................................................... 27 
3.1.1 
Study Duration ............................................................................................ 29 
3.1.2 
Number of Subjects ..................................................................................... 31 
3.2 
Study Procedures ...................................................................................................... 31 
3.2.1 
Site Initiation Procedures ............................................................................ 31 
3.2.2 
Schedule of Events and Assessments.......................................................... 31 
3.2.3 
Screening Visits .......................................................................................... 31 
3.2.4 
Baseline (Day 1) ......................................................................................... 32 
3.2.5 
Weeks 2, 4, and 8 ........................................................................................ 33 
3.2.6 
Week 12 (End-of-Study/Early Termination [EOS/ET]) ............................. 34 
3.2.7 
30-day Safety Follow-up (Telephone; Week 16) ........................................ 34 
4 SELECTION OF SUBJECTS AND CRITERIA FOR WITHDRAWAL ........................ 35 
4.1 
Selection of Subjects ................................................................................................ 35 
4.1.1 
Inclusion Criteria ........................................................................................ 35 
4.1.2 
Exclusion Criteria ....................................................................................... 36 
4.2 
Subject Withdrawal .................................................................................................. 38 
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4.2.1 
Criteria for Subject Withdrawal .................................................................. 39 
5 TREATMENTS ADMINISTERED .................................................................................. 40 
5.1 
Psychosocial Therapy — Non-pharmacologic Intervention Prior to 
Randomization ......................................................................................................... 40 
5.2 
Identity of Investigational Product ........................................................................... 40 
5.3 
Administration of Study Drug .................................................................................. 40 
5.4 
Overdose .................................................................................................................. 40 
5.5 
Dosage Adjustments or Dose Escalation ................................................................. 41 
5.6 
Method of Assigning Subjects to Treatment Groups ............................................... 41 
5.7 
Prior and Concomitant Medications ......................................................................... 41 
5.7.1 
Permitted Concomitant Medications ........................................................... 42 
5.7.2 
Prohibited and Restricted Medications ....................................................... 42 
5.7.3 
Rescue Medications .................................................................................... 42 
5.8 
Blinding .................................................................................................................... 43 
5.9 
Investigational Drug Handling ................................................................................. 43 
5.9.1 
Test Article .................................................................................................. 43 
5.9.2 
Investigational Drug Packaging .................................................................. 43 
5.9.3 
Receipt of Investigational Drug Supplies ................................................... 43 
5.9.4 
Storage of Investigational Drug .................................................................. 43 
5.9.5 
Investigational Drug Dosing ....................................................................... 44 
5.9.6 
Record of Dispensing .................................................................................. 44 
5.9.7 
Accountability ............................................................................................. 44 
6 EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ........................ 45 
6.1 
Efficacy Assessments ............................................................................................... 45 
6.1.1 
Cohen-Mansfield Agitation Inventory (CMAI) .......................................... 45 
6.1.2 
Zarit Burden Interview (ZBI) ...................................................................... 46 
6.1.3 
Neuropsychiatric Inventory – Clinician Rating Scale (NPI-C) .................. 46 
6.1.4 
Mini–Mental State Examination (MMSE) .................................................. 46 
6.1.5 
Modified Alzheimer’s Disease Cooperative Study – Clinical Global 
Impression-Change (mADCS-CGIC) ......................................................... 47 
6.1.6 
Karolinska Sleepiness Scale (KSS) ............................................................ 47 
6.1.7 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
Inventory (ADCS - ADL) ........................................................................... 47 
6.2 
Safety Assessments .................................................................................................. 47 
6.2.1 
Medical and Medication History ................................................................ 48 
6.2.2 
Physical Examinations ................................................................................ 48 
6.2.3 
Vital Signs ................................................................................................... 48 
6.2.4 
Height and Weight ...................................................................................... 48 
6.2.5 
Electrocardiograms ..................................................................................... 48 
6.2.6 
Safety Laboratory Evaluations .................................................................... 48 
6.2.7 
Clinically Significant Abnormalities .......................................................... 50 
6.2.8 
Suicidal Ideation and Behavior ................................................................... 50 
6.3 
Pharmacokinetic Assessments ................................................................................. 51 
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7 ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING .................. 51 
7.1 
Adverse Events ......................................................................................................... 51 
7.2 
Definition of Adverse Events ................................................................................... 51 
7.3 
Serious Adverse Events and Unexpected Adverse events ....................................... 54 
7.3.1 
Elective Procedures and Surgeries .............................................................. 56 
7.4 
Other Reportable Information .................................................................................. 56 
7.5 
Serious Unexpected Suspected Adverse Reaction ................................................... 56 
7.6 
Notification of Serious or Unexpected Adverse Event ............................................ 57 
7.6.1 
Serious Adverse Event Reporting ............................................................... 57 
7.7 
Routine Safety Monitoring ....................................................................................... 58 
7.8 
Pregnancy ................................................................................................................. 58 
7.9 
Emergency Treatment .............................................................................................. 58 
7.10 Emergency Identification of Investigational Drug ................................................... 58 
7.11 Safety Monitoring Committee (SMC) ..................................................................... 59 
8 DATA RECORDING, RETENTION, AND MONITORING .......................................... 59 
8.1 
Case Report Forms and Data Verification ............................................................... 59 
8.2 
Source Documentation ............................................................................................. 59 
8.3 
Availability and Retention of Records ..................................................................... 60 
8.4 
Quality Control and Quality Assurance ................................................................... 60 
8.5 
Subject Confidentiality ............................................................................................. 61 
9 STATISTICAL PLAN ....................................................................................................... 61 
9.1 
General Statistical Methods ..................................................................................... 61 
9.2 
Determination of Sample Size ................................................................................. 62 
9.3 
Handling of Dropouts and Missing Data ................................................................. 62 
9.4 
Subgroup Analyses ................................................................................................... 62 
9.5 
Study Subjects .......................................................................................................... 62 
9.5.1 
Analysis Sets ............................................................................................... 62 
9.5.2 
Subject Accountability and Subject Disposition ......................................... 62 
9.5.3 
Demographic and Pretreatment Characteristics .......................................... 63 
9.6 
Efficacy Analyses ..................................................................................................... 63 
9.6.1 
Primary Endpoint ........................................................................................ 63 
9.6.2 
Secondary Endpoint .................................................................................... 63 
9.6.3 
Exploratory Endpoints ................................................................................ 63 
9.7 
Responder Analyses ................................................................................................. 64 
9.8 
Safety Analyses ........................................................................................................ 65 
9.8.1 
Adverse Events ........................................................................................... 65 
9.8.2 
Clinical Laboratory Values ......................................................................... 65 
9.8.3 
Vital Signs and Body Weight ..................................................................... 65 
9.8.4 
Electrocardiogram ....................................................................................... 65 
9.8.5 
Physical Examinations ................................................................................ 65 
9.8.6 
Suicidal Ideation and Behavior ................................................................... 66 
9.9 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses ...................... 66 
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10 REGULATORY COMPLIANCE ..................................................................................... 66 
10.1 Institutional Review Board ...................................................................................... 66 
10.2 Ethical Conduct of the Study ................................................................................... 66 
10.3 Subject Information and Informed Consent ............................................................. 66 
10.4 Finance, Insurance, and Indemnity .......................................................................... 67 
10.5 Protocol Amendments .............................................................................................. 67 
10.6 Protocol Exceptions and Deviations ........................................................................ 68 
10.7 Termination of the Study ......................................................................................... 68 
10.8 Publication ................................................................................................................ 68 
11 DECLARATION OF INVESTIGATOR........................................................................... 69 
12 REFERENCES .................................................................................................................. 70 
13 APPENDICES ................................................................................................................... 75 
 
LIST OF TABLES 
Table 6–1 Safety Laboratory Evaluations............................................................................... 50 
 
LIST OF FIGURES 
Figure 3-1  Study Design ......................................................................................................... 30 
 
 
 
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LIST OF APPENDICES
Appendix A
Schedule of Events and Assessments.......................................................... 76
Appendix B
International Psychogeriatric Association (IPA) Guidelines ...................... 78
Appendix C
Prohibited and Restricted Concomitant Medications ................................. 79
Appendix D
List of Prohibited CYP3A4 Inhibitors and Inducers ................................... 82
Appendix E
Cohen-Mansfield Agitation Inventory (CMAI)  SAMPLE ...................... 83 
Appendix F
Zarit Burden Interview (ZBI)  SAMPLE .................................................. 87 
Appendix G
 Neuropsychiatric Inventory – Clinician Rating Scale (NPI-C) 
SAMPLE ..................................................................................................... 91
Appendix H
Mini-Mental State Examination (MMSE)  SAMPLE ............................109 
Appendix I
 Modified Alzheimer’s Disease Cooperative Study – Clinical Global
Impression of Change (mADCS-CGIC)  SAMPLE ...............................113 
Appendix J
Karolinska Sleepiness Scale (KSS)  SAMPLE.......................................120 
Appendix K
 Alzheimer’s Disease Cooperative Study-Activities of Daily Living
Inventory (ADCS-ADL)  SAMPLE .......................................................122 
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ABBREVIATIONS AND ACRONYMS 
5-HT2A 
5-hydroxytryptamine (serotonin) receptor 2A 
AD 
Alzheimer’s disease 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living 
Inventory 
AE 
adverse event 
ANCOVA 
analysis of covariance 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CMAI 
Cohen-Mansfield Agitation Inventory 
CNS 
central nervous system 
CT 
computed tomography 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition  
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end-of-study 
ET 
early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
GCAS 
Global Clinician Assessment of Suicidality 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
HDL 
high density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
IPA 
International Psychogeriatric Association 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IXRS 
Interactive Voice/Web Response System 
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 
MMRM 
mixed-model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
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ms 
milliseconds 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NPI 
Neuropsychiatric Inventory 
NPI-C 
Neuropsychiatric Inventory-Clinician Rating Scale 
NPS 
neuropsychiatric symptoms 
PDP 
Parkinson’s disease psychosis 
PK 
pharmacokinetic(s) 
PI 
Principal Investigator 
PP 
per-protocol 
PRN 
pro re nata (as needed) 
QD 
once daily 
QTcF 
Fridericia’s corrected QT 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMC 
Safety Monitoring Committee 
SMT 
safety management team 
SUSAR 
serious unexpected suspected adverse reaction 
TEAE 
treatment-emergent adverse event 
US 
United States 
UTI 
urinary tract infection 
WBC 
white blood cell 
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 
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treatment of persistent aggression with a limited indication (Janssen-Cilag Ltd 2015). Since 
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 
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, 5HT2A receptor blocking compounds. Pimavanserin is one 
such compound that is a highly selective inverse agonist of the 5-hydroxytryptamine 
(serotonin) 2A (5HT2A) receptor that has been evaluated in Phase 3 clinical trials in 
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Parkinson’s disease psychosis (PDP) and has been shown to improve psychosis, caregiver 
burden, and sleep without causing sedation or other significant safety effects, and without a 
detrimental impact on cognition (Cummings et al. 2014).  
1.1 
Investigational Drug 
Pimavanserin tartrate 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, and psychiatric systems. Most events 
were mild to moderate in intensity. The most common CNS events included dizziness 
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(including postural), headache, and somnolence (drowsiness). Common GI disturbances 
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 adverse events (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. An average prolongation of approximately 
5-8 milliseconds (ms) was observed. 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 10 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 have 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 
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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 
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 
study design to evaluate pimavanserin for the treatment of agitation and aggression in AD 
incorporates methods to facilitate an appropriate assessment (Soto et al. 2015). A treatment 
period of 12 weeks will be used for this persistent condition. Use of a psychological 
intervention prior to randomization will identify individuals who benefit from psychological 
treatment alone and do not need pharmacological intervention. The primary and secondary 
measures will assess the efficacy of pimavanserin treatment in reducing agitation and 
aggression, as well as evaluate the effect on caregiver burden. 
2 
OBJECTIVES 
The purpose of this study is to evaluate the safety and efficacy of pimavanserin at doses of 
34 mg and 20 mg, compared to placebo in the treatment of agitation and aggression in 
subjects with probable AD. 
2.1 
Primary Objective and Endpoint 
2.1.1 
Primary Objective 
To evaluate the efficacy of pimavanserin compared with placebo in treatment of agitation and 
aggression after 12 weeks. 
2.1.2 
Primary Endpoint 
Change from Baseline to Week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) total 
score.  
2.2 
Secondary Objective and Endpoint 
2.2.1 
Secondary Objective 
 To evaluate the efficacy of pimavanserin compared with placebo on caregiver burden 
2.2.2 
Secondary Endpoint  
 Change from Baseline to Week 12 in the Zarit Burden Interview (ZBI) total score 
2.3 
Exploratory Objectives and Endpoints 
2.3.1 
Exploratory Objectives 
 To evaluate the efficacy of pimavanserin compared with placebo for the following: 
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 Clinician’s global assessment of treatment benefit 
 Other neuropsychiatric symptoms  
 Functional status  
 Sleep and daytime wakefulness 
 Cognition 
 Need for rescue medication 
 To evaluate the safety and tolerability of pimavanserin  
 To evaluate the plasma concentrations of pimavanserin and the major metabolite 
AC-279  
2.3.2 
Exploratory Endpoints  
2.3.2.1 
Efficacy Endpoints 
 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 individual agitation and aggression domain scores 
 Change from Baseline to Week 12 in Alzheimer’s disease Cooperative Study – 
Activities of Daily Living Inventory (ADCS-ADL) score 
 Change from Baseline to Week 12 in NPI-C total score 
 Change from Baseline to Week 12 in NPI-C sleep disorders domain score 
 Change from Baseline to Week 12 in NPI-C combined delusions and hallucinations 
domain scores 
 Change from Baseline to Week 12 in NPI-C combined dysphoria and 
apathy/indifference domain scores  
 Change from Baseline to Week 12 in individual NPI-C domain scores (other than 
agitation, aggression, and sleep disorders)  
 Change from Baseline in CMAI subscale scores  
 Change from Baseline in Karolinska Sleepiness Scale (KSS) score 
 Change from Baseline in MMSE score 
 Proportion of subjects taking any rescue medication during the 12-week treatment 
period 
2.3.2.2 
Safety Endpoints  
 TEAEs  
 SAEs 
 Withdrawals due to AEs 
 Global Clinician Assessment of Suicidality (GCAS) 
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 Clinically important changes in other safety assessments 
 Vital signs 
 Weight 
 Clinical laboratory results (hematology, serum chemistry, urinalysis) 
 Physical examinations 
 Electrocardiograms (ECGs) 
2.3.2.3 
Pharmacokinetic Endpoints 
 Plasma concentration of pimavanserin and AC-279 
3 
STUDY DESIGN 
A schematic of the study design is presented in Figure 3-1. 
3.1 
Overall Study Design 
This study will be conducted as a Phase 2, 12-week, randomized, double-blind, placebo-
controlled, multicenter, outpatient study in subjects with a diagnosis of probable AD, 
according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) guidelines 
(McKhann et al. 2011), who have clinically significant agitation/aggression. 
Only subjects who have been at their current location (at home or in an assisted living 
facility) for at least 3 weeks prior to Screening and plan to remain at the same location for the 
duration of the trial may enter the study. Subjects must have a reliable study partner/caregiver 
(e.g., relative, housemate, close personal friend, or professional caregiver) who has 
interaction with the subject at least 3 times a week on 3 separate days. The study 
partner/caregiver must: 
 be willing and able to accompany the subject to all clinic visits,  
 be capable of routinely monitoring and reporting study drug use, and 
 be regarded by the Investigator as sufficiently informed to report accurately on the 
subject’s behavioral and functional status. 
Every attempt should be made to keep the same individual as the reliable study 
partner/caregiver throughout the duration of the study. If a subject’s study partner/caregiver 
discontinues/stops participating in the study, a suitable replacement caregiver must be 
identified for that subject to remain in the study. 
Study periods:  
 Screening  
 Double-blind treatment (Day 1 through 12 weeks of treatment) 
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 Safety follow-up period (~30 days after the last dose of study drug) 
Screening Period 
The screening period will be at least 2 weeks in duration and may be extended to 4 weeks, if 
needed. Subjects on antipsychotic medication at the beginning of the screening period will 
discontinue that medication (wash-out of at least 5 half-lives) during the screening period. 
Subjects who screen fail will be allowed to rescreen with agreement of the Medical Monitor. 
Subject randomization will occur at the end of the screening period for those who continue to 
meet enrollment criteria. 
All medicinal products containing psychotropic agents, except those specified in the protocol, 
are prohibited during the treatment period. Treatment with an antipsychotic medication must 
be discontinued 2 weeks or at least 5 half-lives (whichever is longer) prior to the Baseline 
visit. Use of permitted medications (e.g., antidepressants) should be stable at least 4 weeks 
prior to Baseline (Day 1) and should be expected to remain stable throughout the study (see 
Section 5.7). If taking cholinesterase inhibitors and/or memantine, doses should be stable at 
least 12 weeks before Baseline (Day 1) and should be expected to remain stable throughout 
the study. 
During the Screening Period, subjects will be assessed for study eligibility. 
Subjects are required to meet the following criteria: 
 Mini-Mental State Examination (MMSE) score of 5 to 26 (inclusive) at the Screening 
Visit 
 Neuropsychiatric Inventory – Clinician Rating Scale (NPI-C) combined agitation and 
aggression domain score of ≥14 at both the Screening and Baseline visit  
Double-blind, Randomized Treatment Period 
The Baseline visit (Day 1) may occur as soon as all screening procedures are completed and 
subject eligibility has been confirmed. Subjects will be randomly assigned (1:1:1) to 
pimavanserin 34 mg, pimavanserin 20 mg, or matching placebo, and stratified according to 
geographic region (North America, Europe, or Rest of World). Subjects will attend a 
prescheduled clinic visit on Day 1 (Baseline), followed by clinic visits at 2, 4, 8, and 
12 weeks after randomization. If a subject should discontinue prematurely from the study for 
any reason, every effort should be made to complete all of the procedures included in the 
end-of-study/early termination (EOS/ET) visit (Week 12; Visit 5). 
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Follow-up of Study Completers  
Subjects who successfully complete the 12-week treatment period can enroll in an open-label 
safety extension study if they qualify. For subjects who discontinue prematurely from the 
study or who do not enroll in the open-label extension study, a follow-up safety assessment 
will be conducted by telephone call approximately 30 days after the last dose of study drug. 
3.1.1 
Study Duration 
The duration of participation for individual subjects will be up to approximately 20 weeks. 
Each subject will participate in a 2- to 4-week screening period, a 12-week treatment period, 
and a 30-day safety follow-up (telephone call) for those subjects who discontinue 
prematurely from the study or who do not enroll in the open-label extension study. The end of 
the clinical trial will be when the last subject completes the last scheduled assessment (i.e., 
30-day follow-up or enrolled in the extension study). 
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Figure 3-1 Study Design 
 
 
a 
For subjects taking antipsychotic medication, the screening period may be extended to 4 weeks if necessary for wash-out of at least 5 half-lives of the 
medication. 
AD=Alzheimer’s disease; NIA-AA=National Institute on Aging-Alzheimer’s Association (McKhann et al. 2011); QD=once daily  
 

Pimavanserin 34 mg QD 

Pimavanserin 20 mg QD 

Placebo QD 
Blinded study treatment to end-of-study  
5 clinic visits for study assessments (Baseline and Weeks 2, 4, 8, and 12) 
 
 
~30 days 
off-drug 
30-Day Follow-
Up 
(
)
12-Week, Randomized, Double-Blind, Placebo-Controlled 
Treatment Period 
Randomization 
Day 1 (Baseline) 
Diagnosis of probable 
AD according to 
NIA-AA guidelines 
Psychosocial therapy 
Screening Perioda 
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3.1.2 
Number of Subjects 
The original planned sample size was approximately 432. For business reasons, not related to 
safety, the enrollment (randomization) of new subjects into the study was stopped after 
111 subjects were randomized. The last subject was randomized into the study on 
November 2, 2017. This study enrolled subjects with probable AD who have 
agitation/aggression. On the first day of the randomized treatment phase (Baseline), eligible 
subjects were randomly assigned to receive pimavanserin 34 mg per day, pimavanserin 
20 mg per day, or placebo daily in a 1:1:1 ratio, according to a computer-generated 
randomization schedule. The randomization was stratified according to geographic region 
(North America, Europe, or Rest of World). 
3.2 
Study Procedures 
3.2.1 
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 ICFs prior to 
undergoing screening. Each subject who signs an ICF will be assigned a unique identification 
number. 
3.2.2 
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 (Appendix A), if necessary.  
3.2.3 
Screening Visits 
The screening period will be 2 to 4 weeks in duration. Subjects on antipsychotic medication 
at the beginning of the screening period will discontinue use (wash-out) during the screening 
period. For these subjects, a 28-day screening period is allowed in order to accommodate 
wash-out of antipsychotics that require up to 4 weeks. Subjects who screen fail will be 
allowed to rescreen with agreement of the Medical Monitor. Rescreened subjects must go 
through all screening procedures as if they have never been screened before. During the 
screening period, study partners/caregivers will be provided instruction for implementing a 
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psychosocial therapy for the duration of the screening period. Subject randomization will 
occur at the end of the screening period for those who continue to meet enrollment criteria. 
Informed consent must be obtained and the ICF signed before screening procedures 
commence. The monitoring and recording of AEs will commence after a subject has signed 
the ICF. 
Screening evaluations will include the following: 
 Demography 
 Medical and AD history 
 Physical examination  
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight and height  
 12-lead ECG (triplicate) 
 Laboratory profiles (hematology, serum chemistry, and urinalysis [if able]; 
vitamin B12 level) 
 Serum pregnancy test for all women of childbearing potential. Results must be 
negative for subjects to be eligible for the study.  
 NPI-C agitation and aggression 
 MMSE 
 Review of magnetic resonance imaging (MRI) or computed tomography (CT) scan 
(brain imaging) taken during or subsequent to diagnosis of probable AD, or during the 
screening period (prior to Baseline [Day 1])  
 Study partners/caregivers will be provided with instruction for psychosocial therapy 
and will carry out activities for psychosocial therapy (telephone contact will occur 
weekly to support the therapy) 
 Review of current medications/treatments 
 Assessment of AEs 
 Global Clinician Assessment of Suicidality (GCAS) 
3.2.4 
Baseline (Day 1) 
On Day 1 after screening procedures are completed and reviewed (e.g., acceptable clinical 
laboratory tests), the subject will be evaluated for continued eligibility and if qualified, may 
enter the treatment phase and receive the first dose study drug. Subjects will complete the 
following procedures at Baseline: 
 Vital signs (pre-dose, sitting [at least 3 minutes] blood pressure, pulse, respiratory 
rate, and temperature) 
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 Weight 
 12-lead ECG (single recording) 
 Laboratory profiles (hematology, serum chemistry, and urinalysis [if able])  
 Urine pregnancy test for all women of childbearing potential 
 Blood sampling for PK assessments  
 CMAI 
 ZBI 
 NPI-C (complete) 
 MMSE 
 mADCS-CGIC 
 KSS  
 ADCS-ADL  
 Assessment of concomitant medications/treatments 
 Assessment of AEs 
 GCAS 
 Randomization 
 Dispense and administer first dose of study drug 
 
Each subject will be assigned study drug according to the randomization schedule. 
The first dose will be administered at the clinic; study drug kits will then be 
dispensed to the subject to take home. It is recommended that the subject take the 
study drug at approximately the same time each day. 
3.2.5 
Weeks 2, 4, and 8 
Subjects will have the following procedures completed at each visit: 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 Weight 
 12-lead ECG (Week 4 only, single recording) 
 Laboratory profiles (hematology, serum chemistry, and urinalysis [if able]) (Week 4 
only) 
 Urine pregnancy test for all women of childbearing potential (Week 4 only) 
 Blood sampling for PK assessments (Weeks 2 and 4 only; if collection at Week 2 
does not occur, then collection should be attempted at Week 8) 
 CMAI 
 ZBI 
 NPI-C agitation and aggression  
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 MMSE (Weeks 4 and 8 only) 
 mADCS-CGIC 
 KSS  
 Assessment of concomitant medications/treatments 
 Assessment of AEs 
 GCAS 
 Study drug dispensing and accountability 
 
Study drug kits dispensed at Week 4 and Week 8 only (Week 2 does NOT require 
study drug to be dispensed). 
3.2.6 
Week 12 (End-of-Study/Early Termination [EOS/ET]) 
 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 
 Blood sampling for PK assessments  
 CMAI 
 ZBI 
 NPI-C (complete) 
 MMSE 
 mADCS-CGIC 
 KSS  
 ADCS-ADL  
 Assessment of concomitant medications/treatments 
 Assessment of AEs 
 GCAS 
 Study drug accountability 
3.2.7 
30-day Safety Follow-up (Telephone; Week 16) 
 Assessment of concomitant medications/treatments  
 Assessment of AEs 
 GCAS 
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Note: A 30-day safety follow-up is to be completed for those subjects who discontinue 
prematurely from the study or who do not enroll in the open-label extension study. 
4 
SELECTION OF SUBJECTS AND CRITERIA FOR WITHDRAWAL 
4.1 
Selection of Subjects 
Subjects must meet 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 post-randomization 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.  
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. Male or female, 50 years of age or older  
3. Has a diagnosis of probable AD according to the National Institute on Aging-Alzheimer’s 
Association (NIA-AA) guidelines 
4. Meets criteria for agitation according to the International Psychogeriatric Association 
(IPA) guidelines (see Appendix B).  
5. Has an MRI or CT scan (brain imaging) taken during or subsequent to diagnosis of 
probable AD, or during the screening period (prior to Baseline)  
6. Has a MMSE score of 5 to 26 (inclusive) at Screening 
7. Has agitation/aggression defined as a Neuropsychiatric Inventory – Clinician rating scale 
(NPI-C) combined agitation and aggression domain score of ≥14 at both the Screening 
and Baseline Visits 
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8. Lives at home or in an assisted living or care facility (but has the capacity to visit the 
clinic as an outpatient). Subjects must have been at their current location for at least 
3 weeks prior to Screening and plan to remain at the same location for the duration of the 
trial. 
9. 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 must: 
 
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.  
10. 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  
11. 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 
12. Both subject and study partner/caregiver are willing and able to participate in all 
scheduled evaluations and complete all required tests 
13. If taking antidepressants, has been on a stable dose for at least 4 weeks prior to the 
Baseline visit and should expect to remain on a stable dose throughout the trial 
14. If taking cholinesterase inhibitors and/or memantine, has been on a stable dose for at least 
12 weeks prior to the Baseline visit and should expect to remain on a stable dose 
throughout the trial 
15. 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, for at least 1 month prior to randomization, 
during the study, and 1 month following completion of the study 
Females of childbearing potential must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at Screening and a negative urine hCG pregnancy test 
at Baseline  
4.1.2 
Exclusion Criteria 
1. The agitation/aggression is attributable to concomitant medications, environmental 
conditions, substance abuse, or active medical or psychiatric condition 
2. Has a current major depressive disorder episode (within 3 months) according to the 
Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria  
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3. Treatment with an antipsychotic medication within 2 weeks of Baseline visit or 
5 half-lives, whichever is longer  
Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study unless discontinuation of the medication is deemed to be 
clinically appropriate (e.g., symptoms are not well-controlled or the subject cannot 
tolerate the current medication). 
4. Has brain abnormalities seen on an MRI or CT scan (brain imaging) taken during or 
subsequent to diagnosis of probable AD, that can be attributed to diseases or processes 
other than AD, including but not limited to: 
 
multiple lacunar infarcts or evidence of a single prior infarct >1 cm3; 
 
intracranial mass lesion (including but not limited to meningioma [>1 cm3 with 
evidence of peritumoral edema]); or 
 
glioma, vascular malformation, or macrohemorrhage. 
5. Subject or study partner/caregiver has a medical condition (e.g., hearing, vision 
impairments) that would impair the ability to perform the study assessments.  
6. Subject requires treatment with a medication prohibited by the protocol (see Section 5.7, 
Appendix C, and Appendix D) 
7. Subject has had a myocardial infarction within the last 6 months prior to Screening 
8. Subject has a known history or symptoms of long QT syndrome  
9. Subject has a QRS interval <120 ms and whose Fridericia’s corrected QT interval (QTcF) 
is >460 ms at Screening or at Baseline OR subject has a QRS interval ≥120 ms and QTcF 
is >480 ms at Screening or at Baseline 
10. Has clinically significant laboratory abnormalities that in the judgment of the Investigator 
or Medical Monitor would jeopardize the safe participation of the subject in the study  
11. Has a history of a significant psychotic disorder prior to or concomitant with the 
diagnosis of probable AD including, but not limited to, schizophrenia or bipolar disorder 
12. Subject is 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  
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13. Has participated in or is participating in a clinical trial of any investigational drug, device, 
or intervention, and within 4 weeks (or 5 half-lives, whichever is longer) of the Baseline 
visit 
14. Subject with sensitivity to pimavanserin or its excipients 
15. Subject has previously participated in a clinical study with pimavanserin 
16. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for the 
study 
17. 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)  
18. Has a body mass index (BMI) of <18.5 
19. Has an abnormal vitamin B12 result at Screening or within the prior 12 months prior to 
Visit 1 (Screening) that has not been successfully treated 
20. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 or 4 based on 
Investigator’s assessment of behavior within the last 3 months at Screening or since-last-
visit at Baseline 
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 legally authorized representative because the subject is not 
competent to provide informed consent, the authorized representative 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 legally authorized 
representative. 
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 
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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 AEs(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 legally authorized 
representative (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 EOS/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 study 
partner/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 study partner/caregiver should 
be documented. 
For subjects who continue to be followed for safety, SAEs should continue to be reported as 
described in Section 7.6.1. 
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 the Week 12 (EOS/ET) visit, or until the Week 16 
Safety follow-up visit for those subjects who do not enter the safety extension study, 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. 
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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 Week 12 (EOS/ET) visit as outlined in Appendix A. Every 
attempt will be made to complete the 30-day safety follow-up telephone 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 
Psychosocial Therapy — Non-pharmacologic Intervention Prior to 
Randomization 
During the screening period, subjects will receive a structured psychosocial interaction with 
the designated study partner/caregiver for a recommended target of 5 times per week 
(minimum of 3 times per week). This psychological intervention is intended to aid the patient 
and caregiver in managing the patient’s neuropsychiatric symptoms. Study partner/caregivers 
will be instructed on the therapy by trained site personnel and will have weekly supportive 
telephone contacts. The intervention should be conducted for the duration of the screening 
period. 
5.2 
Identity of Investigational Product 
Drug 
Administration 
Form 
Total 
Strength 
Provided as 
Route of 
Administration 
Pimavanserin 
Tablet 
34 mg 
2×17 mg tablets 
Oral 
Pimavanserin 
Tablet 
20 mg 
2×10 mg tablets 
Oral 
Placebo 
Tablet 
N/A 
2×Placebo tablets 
Oral 
N/A = not applicable 
5.3 
Administration of Study Drug  
Eligible subjects who are randomized will receive either pimavanserin 34 mg per day 
pimavanserin 20 mg per day or placebo daily for up to 12 weeks. 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. 
5.4 
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 are to be captured as protocol deviations. 
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5.5 
Dosage Adjustments or Dose Escalation 
No dosage adjustments or dose escalation will be allowed for pimavanserin throughout the 
study. 
5.6 
Method of Assigning Subjects to Treatment Groups 
Subjects who have signed the ICF, completed screening procedures and are entered into the 
study or screen failed, will be entered into the electronic data capture (EDC) system. At the 
time of screening, the site will assign a 6-digit site-specific sequential screening number. The 
subject identification number will consist of a 3-digit original site number followed by a 
unique 3-digit screening number. Once entered into the study, each subject will keep this 
same subject identification number throughout the study. Upon randomization, a unique 
study-specific randomization number will be assigned by an Interactive Voice/Web Response 
System (IXRS).  
On Day 1 of the treatment phase, eligible subjects who meet all inclusion and none of the 
exclusion criteria will receive pimavanserin 34 mg per day, pimavanserin 20 mg per day or 
daily placebo according to a computer-generated randomization schedule. Subjects will be 
randomized in a 1:1:1 ratio to 1 of 3 treatment groups (pimavanserin 34 mg, pimavanserin 
20 mg, or placebo), and stratified according to geographic region (North America, Europe, or 
Rest of World). The assignments will be blinded to all study subjects, study 
partners/caregivers, Investigators, raters, site personnel, and Sponsor personnel. 
5.7 
Prior and Concomitant Medications 
All medications used up to 12 weeks prior to Baseline (Day 1) through Visit 6 (telephone 
visit) or ET are to be recorded.  
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 (unless the subject is receiving treatment for a medical emergency). 
The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. The Sponsor and Investigator, or designee, 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. 
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5.7.1 
Permitted Concomitant Medications 
Subjects will be allowed to continue permitted medications (e.g., antidepressants, dietary 
supplements, etc.) as long as they have been stable on the same dose for at least 4 weeks prior 
to Baseline (Day 1) and should expect to remain on this dose for the duration of the study. 
Cholinesterase inhibitors and/or memantine must be stable for at least 12 weeks prior to 
Baseline and should expect to remain unchanged until the subject’s final visit (EOS/ET). 
5.7.2 
Prohibited and Restricted Medications 
Restrictions for concomitant medications should be followed between the initial screening 
visit and the Week 12 (EOS/ET) visit as specified in Appendix C and Appendix D. 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 C. 
Treatment with an antipsychotic medication must be discontinued 2 weeks or at least 
5 half-lives (whichever is longer) prior to the Baseline (Day 1) visit. 
If a subject is on a medication prohibited by the protocol, the medication should be 
discontinued only if it is determined by the Investigator to be clinically appropriate (e.g., if 
the subject's symptoms are not well-controlled or if the subject cannot tolerate the current 
medication). 
5.7.3 
Rescue Medications 
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 lorazepam will be documented as 
a rescue medication, even if given to subjects for symptoms other than agitation and 
aggression. Lorazepam at a maximum dose of up to 2 mg per 24-hour period will be allowed 
as rescue medication on an intermittent or PRN basis only, 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 after randomization in any 4-week period. If lorazepam is not available, 
another intermediate acting benzodiazepine may be used at doses equivalent to lorazepam 
doses. 
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5.8 
Blinding 
Treatment assignment will be double-blind where neither the subjects, study 
partners/caregivers, Sponsor personnel who oversee the study, nor the Investigator and study 
personnel will know which treatment is assigned to each subject. See Section 7.10 for details 
regarding medical emergency unblinding procedures.  
5.9 
Investigational Drug Handling 
5.9.1 
Test Article 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin tablets include the active 
compound (pimavanserin) and the following excipients:
 
 
Placebo tablets contain all of the same excipients as pimavanserin 10 mg and 17 mg tablets 
except for the active compound.  
Pimavanserin and placebo used for the tablets are manufactured under current Good 
Manufacturing Practices compliance by
 
5.9.2 
Investigational Drug Packaging 
Pimavanserin will be provided as 10 mg and 17 mg strength tablets; matching placebo tablets 
will also be provided. ACADIA or its designee will supply the pimavanserin and placebo 
tablets.  
During the treatment period, study drug will be supplied in kits which will contain 4 blister 
cards; each kit is sufficient for a 4-week supply. Each blister card contains 20 tablets. Each 
blister card contains study drug for 10 days. 
5.9.3 
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 provide a copy of 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. 
5.9.4 
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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5.9.5 
Investigational Drug Dosing 
The first dose of study drug will be administered at the clinic; study drug kits will then be 
dispensed to the subject to take home. It is recommended that the subject take the study drug 
at approximately the same time each day until the Week 12 (EOS/ET) visit. Each daily dose 
consists of 2 individual tablets that should be taken together. Study drug can be taken with or 
without food consumption. 
5.9.5.1 
Treatment Period 
At Baseline (Day 1), subjects will be randomized to double-blind study treatment and take 
their first dose from a new drug kit while at the clinic, and will be provided with the drug kit 
to take home. Study personnel will dispense study drug to subjects by accessing the IXRS. 
Additional kits will be provided at Week 4 and Week 8 clinic visits. Investigational drug 
supplies will be labeled in accordance with all applicable guidelines and/or regulations and 
will be blinded as to subject treatment assignment. 
5.9.6 
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.  
5.9.7 
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 used/empty kits, blister cards and unused tablets to the Investigator at 
regularly scheduled clinic visits 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. 
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. 
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6 
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS 
6.1 
Efficacy Assessments  
The following efficacy endpoints will be assessed in this study using the measures described 
in this section: Cohen-Mansfield Agitation Inventory (CMAI), Zarit Burden Interview (ZBI), 
Neuropsychiatric Inventory–Clinician Rating Scale (NPI-C), Mini-Mental State Examination 
(MMSE), modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression of 
Change (mADCS-CGIC), Karolinska Sleepiness Scale (KSS), and Alzheimer’s Disease 
Cooperative Study–Activities of Daily Living Inventory (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 (e.g., Baseline visit to Week 2, Week 2 to 
Week 4, Week 4 to Week 8, and so on).  
6.1.1 
Cohen-Mansfield Agitation Inventory (CMAI)  
The CMAI was developed to assess the frequency of manifestations of agitated behaviors in 
elderly persons (Cohen-Mansfield 1989; see Appendix E). 
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 in this study is to be completed by interview of the 
caregiver. Ratings are inclusive of the 2 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 Weeks 2, 4, 8, and 12 (EOS/ET). 
Recording of CMAI Interviews 
An in-study endpoint reliability program will be implemented. For the CMAI, caregiver 
interviews will be collected using digital recording equipment. 
 a company 
contracted by ACADIA, will collect and review the interviews to assess thoroughness of the 
interview and monitor the appropriate administration and scoring. 
The rating scale assessments and recordings of the caregiver interviews will be sent in a 
secure manner for quality control, training, and calibration (standardization) purposes. 
A unique subject number will be used to identify the recorded materials; subject identifying 
information will not be used. Qualified personnel from
 responsible for reviewing 
the information may listen to these recordings. The recordings will be kept confidential and 
no other person will be allowed to listen to the recordings. 
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6.1.2 
Zarit Burden Interview (ZBI) 
The ZBI was designed to assess the stresses experienced by caregivers of patients with 
dementia (Zarit et al. 1980; see Appendix F). The ZBI can be self-reported or 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, and 12 (EOS/ET).  
Note: Professional caregivers do not complete this form.  
6.1.3 
Neuropsychiatric Inventory – Clinician Rating Scale (NPI-C) 
The NPI-C was developed to assess psychopathology in patients with dementia 
(de Medeiros et al. 2010; see Appendix G). The NPI-C evaluates NPS across many 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, which includes agitation and aggression domains, will be administered 
by a qualified rater at Baseline (Day 1) and at Weeks 12 (EOS/ET) and the NPI-C agitation 
and aggression domains will be administered at Screening, and at Weeks 2, 4, and 8. 
6.1.4 
Mini–Mental State Examination (MMSE)  
The MMSE is a brief 30-point questionnaire that is used to quantitatively assess cognition 
(Folstein et al. 1975; see Appendix H). 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 Screening, Baseline 
(Day 1), and at Weeks 4, 8, and 12 (EOS/ET). 
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6.1.5 Modified Alzheimer’s Disease Cooperative Study – Clinical Global Impression-
Change (mADCS-CGIC)  
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 I). 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 
interview, using a standardized 7-point scale (1=marked improvement to 7=marked 
worsening). 
The mADCS-CGIC will be administered at Baseline (Day 1) and at Weeks 2, 4, 8, and 12 
(EOS/ET).  
6.1.6 
Karolinska Sleepiness Scale (KSS)  
The KSS is a self-reported subjective measure of a subject's level of drowsiness 
(Akerstedt and Gillberg 1990; 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 
(Day 1) and at Weeks 2, 4, 8, and 12 (EOS/ET). 
6.1.7 Alzheimer’s Disease Cooperative Study - Activities of Daily Living Inventory 
(ADCS - ADL) 
The ADCS-ADL is an inventory to assess activities of daily living in subjects with AD 
(Galasko et al. 1997; see Appendix K). 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 (Day 1) and 
at Week 12 (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, height and weight, ECGs, 

 
 
suicidal ideation and behavior, and safety laboratory evaluations according to the schedule of 
events and assessments in Appendix A. 
6.2.1 
Medical and Medication History 
A thorough medical history will be obtained by interviewing each subject at the Screening 
visit. A careful review of current, recent, and past medications with each subject will also be 
performed. Medication history will be documented, including concomitant medications used 
throughout the screening period. 
6.2.1.1 
Alzheimer’s Disease History 
A thorough subject history specific to their diagnosis of probable AD will be obtained by 
interviewing each subject at the Screening visit. Current and past treatments, medication 
history, or therapies that are specific to their diagnosis of probable AD will be recorded.  
6.2.2 
Physical Examinations 
Physical and neurological examinations will be conducted at Screening and at the Week 12 
(EOS/ET) visit. At the Investigator’s discretion, examinations may include a review of body 
systems (urogenital exam 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). 
6.2.3 
Vital Signs 
Vital signs (pre-dose [baseline only], sitting [at least 3 minutes] blood pressure, pulse rate, 
temperature, and respiratory rate) should be performed at Screening, Baseline (Day 1), and 
Weeks 2, 4, 8, and 12 (EOS/ET). 
6.2.4 
Height and Weight 
Height will be measured at Screening only. Weight will be measured at Screening, Baseline 
(Day 1) and Weeks 2, 4, 8, and 12 (EOS/ET). 
6.2.5 
Electrocardiograms 
A 12-lead ECG will be performed in triplicate at Screening. Single recordings will be 
performed at Baseline (Day 1), and Weeks 4 and 12 (EOS/ET). 
6.2.6 
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 Screening, Baseline (Day 1), 
Week 4, and at Week 12 (EOS/ET). With the exception of the Screening visit, all attempts 
should be made for subjects to fast for 12 hours before laboratory evaluations are done. 
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For all female subjects of childbearing potential, a serum pregnancy test must be performed 
at the Screening visit. A urine pregnancy test will be performed at Baseline (Day 1), Week 4, 
and at Week 12 (EOS/ET). Pregnancy tests must be negative at Screening and Baseline 
(Day 1) for study entry. 
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, and as presented 
in Table 6–1. 
 
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 
 
Serum pregnancy test for women of childbearing potential 
 
Vitamin B12 assay (completed only at Screening) 
 
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 of child-bearing potential. 
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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. 
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. 
Table 6–1 Safety Laboratory Evaluations 
Visit 
Tests* 
Screening (initial visit) 
CHEM, CBC, UA, and serum pregnancy 
Baseline (Day 1) 
CHEM, CBC, UA , and urine pregnancy 
Week 4 
CHEM, CBC, UA, and urine pregnancy 
Week 12 
CHEM, CBC, UA, and urine pregnancy  
Abbreviations: CBC=complete blood count; CHEM=serum chemistry; UA=urinalysis 
* Urinalysis requirement not applicable to subjects who are unable to provide urine sample (e.g., incontinent subjects). 
Additional safety testing may be performed at the discretion of the Principal Investigator (PI) 
or designate. 
6.2.7 
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 may be recorded as an AE. 
Laboratory results will be reported to the Investigator who will review abnormal laboratory 
findings for clinical significance. Further details on blood and urine sample collection are 
specified in the laboratory manual. 
6.2.8 
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 Visit 1 (Screening) lifetime suicidality and suicidality for 
the past 3 months will be assessed and at all other visits, suicidality since the previous visit 
will be assessed.  
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6.3 
Pharmacokinetic Assessments 
Blood samples will be collected via venipuncture at the Baseline visit (pre-dose), and at 
Weeks 2, 4, and 12 (EOS/ET) for plasma concentration measurements of pimavanserin and 
its metabolite (AC-279). (Note: If collection at Week 2 does not occur, then collection should 
be attempted at Week 8.) In addition, if possible, blood samples will be collected from 
subjects who experience an SAE or an AE leading to discontinuation, as soon as possible 
after experiencing the event.  
For all PK samples (scheduled and unscheduled), the actual dates and times of administration 
of the last 3 doses of study drug before PK sample collection will be recorded on the CRF, if 
known. For samples collected from subjects who experience an SAE or an AE leading to 
discontinuation, the date and time of the last dose prior to the SAE or AE should also be 
recorded. 
Blood samples will be processed for determination of pimavanserin serum concentrations. At 
each timepoint, blood will be collected, processed, and serum samples will shipped to the 
central laboratory for storage and to the bioanalytical laboratory for analysis. A laboratory 
manual will be provided for sample processing, storage, and shipping procedures. Plasma 
concentration data will not be analyzed until the official unblinding of the clinical database at 
the end of the study. 
7 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING 
7.1 
Adverse Events 
Adverse events will be recorded from the time informed consent is obtained. For subjects 
who enroll in the open-label extension study, AEs from this study will be recorded through 
the completion of procedures at the Week 12 (EOS/ET) visit. Any AE occurring thereafter 
will be recorded in the open-label extension study. For subjects who complete the study or 
prematurely discontinue from the study and do not enter the open-label study, AEs will be 
recorded through the follow-up safety assessment (conducted by telephone call) 
approximately 30 days after the last dose of study drug. All AEs must be either resolved or 
stable at Week 12 (EOS/ET). If 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 
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(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 AE.  
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, but 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: 
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 
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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 AEs 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 
Action Taken with Investigational Drug 
 Dose not changed: No change in study drug 
 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 
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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.  
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 
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 Prolongs existing hospitalization 
 Is a congenital anomaly or birth defect (in an offspring) 
 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 
 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. 
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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. 
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 5.4 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 
Serious Unexpected Suspected Adverse Reaction 
A serious unexpected suspected 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. 
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7.6 
Notification of Serious or Unexpected Adverse Event 
Per Food and Drug Administration (FDA) safety reporting requirements (CDER 2012) a 
Sponsor must continue to “promptly” review all safety information obtained from foreign or 
domestic sources. However, the sources of information listed in the regulation has expanded 
to include “any clinical or epidemiological investigations, animal or in vitro studies, reports 
in the scientific literature, and unpublished scientific papers, as well as reports from foreign 
regulatory authorities and reports of foreign commercial marketing experience for drugs that 
are not marketed in the United States.”  
7.6.1 
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 
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. 
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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. 
Serious AEs should also be reported to the IRB/EC according to local regulations.  
7.7 
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 (blinded) non-serious AEs, clinical 
laboratory data, and other relevant safety data. 
7.8 
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 7.6.1. 
7.9 
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 
subject/study partner/caregiver when medical care is needed for intercurrent illness(es) of 
which the Investigator becomes aware. 
7.10 
Emergency Identification of Investigational Drug 
The Investigator may break the blind in the event of an immediate medical emergency if it is 
considered necessary for the care of the subject. The Investigator should contact the study 
Medical Monitor to discuss the event, but this need not be prior to unblinding the subject.  
In an emergency situation, the subject’s treatment assignment may be obtained by the 
Investigator from the Interactive Voice/Web Response System (IXRS). Details of the process 
to be followed are provided in the IXRS Manual. In the event that the IXRS is used to 
perform a code break, ACADIA (and/or its designee) will be notified immediately via an 
automated notification from the IXRS that an unblinding has occurred. The notification only 
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alerts ACADIA (and/or its designee) that the unblinding occurred, and does not include any 
information about the unblinded subject’s treatment assignment. 
7.11 
Safety Monitoring Committee (SMC) 
A Safety Monitoring Committee (SMC) will review safety and clinical outcome data, 
including AE and SAE data at regular intervals throughout the study. The SMC will be 
independent of the Sponsor and the Investigators, and will be empowered to recommend 
stopping or modifying the study due to safety concerns, but not for efficacy or futility.  
The SMC may review blinded, unblinded, and partially unblinded data, but the Sponsor and 
the Investigators will remain blinded to the data provided to the SMC until the official 
unblinding of the clinical database at the end of the study. 
In addition to their regular reviews of safety and clinical outcome data, the SMC will review 
formal comparisons of the rates of SAEs including deaths between the treatment groups. 
The membership of the SMC will consist of clinical and statistical experts, and its mandate 
will be described in the SMC charter. Full details concerning the statistical methodology, as 
well as the frequency of interim safety analyses, will also be described in the SMC charter. 
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 
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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), and 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. 
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. 
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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. 
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). 
The original planned sample size was approximately 432. For business reasons, not related to 
safety, the enrollment (randomization) of new subjects into the study was stopped after 
111 subjects were randomized. The last subject was randomized into the study on 
November 2, 2017. As a result, the study is not powered to definitively detect differences 
between the treatment groups and the summaries will be descriptive in nature. No hypothesis 
testing is planned. 
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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 
containing the results of the data summaries will follow appropriate standard operating 
procedures (SOPs). 
9.2 
Determination of Sample Size 
The original planned sample size was approximately 432. For business reasons, not related to 
safety, the enrollment (randomization) of new subjects into the study was stopped after 
111 subjects were randomized. The last subject was randomized into the study on 
November 2, 2017. As a result, the study is not powered to definitively evaluate 
efficacy measures and only descriptive summaries will be provided. 
9.3 
Handling of Dropouts and Missing Data 
Handling of missing values will be described in detail in the SAP. For the responder analyses, 
two sets of analyses 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 includes all randomized subjects who received at least 1 dose of 
study drug (pimavanserin or placebo). Subjects will be summarized based on the treatment 
which they actually received. The Safety Analysis Set will be used for all safety analyses. 
The Full Analysis Set includes all randomized subjects who received at least 1 dose of study 
drug and who have both a baseline value and at least 1 post-baseline value for the CMAI total 
score. Subjects will be summarized based on their randomized treatment. The Full Analysis 
Set will be used for the summaries of all efficacy endpoints. The Per-protocol (PP) Analysis 
Set will be defined prior to unblinding the study for the final summaries. Subjects will be 
summarized based on their randomized treatment. 
9.5.2 
Subject Accountability and Subject Disposition 
Study enrollment by center will be summarized. The number and percentage of subjects 
randomized and treated in the study will be presented, together with the number and 
percentage of subjects in each analysis set, and 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. 
Listings of the reasons for exclusion from analysis sets will also be provided. 
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9.5.3 
Demographic and Pretreatment Characteristics 
Demographics and pretreatment characteristics of each treatment group will be summarized 
using descriptive statistics and corresponding listings will be provided. 
9.6 
Efficacy Analyses 
All efficacy endpoints will be summarized by treatment group using descriptive statistics. No 
hypothesis testing is planned. Details regarding the scoring for each instrument will be 
provided in the SAP.  
9.6.1 
Primary Endpoint 
The primary endpoint is the change from Baseline to Week 12 in CMAI total score. The 
primary endpoint will be summarized based on the Full Analysis Set.  
The CMAI total score will be summarized using mixed-model repeated measures (MMRM). 
The dependent variable will be the change from baseline in the CMAI total score. The 
independent variables in the model will include the following: treatment group (pimavanserin 
34 mg, pimavanserin 20 mg, or placebo), visit (Weeks 2, 4, 8, and 12), the treatment-by-visit 
interaction, the baseline CMAI total score, the Baseline-by-visit interaction, and geographic 
region (North America, Europe, or Rest of World). 
9.6.2 
Secondary Endpoint 
The secondary endpoint is the change from Baseline to Week 12 in the ZBI total score. This 
will be summarized using an MMRM model similar to that described above for the primary 
endpoint, except that the baseline ZBI total score will be included in the MMRM model 
instead of the baseline CMAI total score. 
9.6.3 
Exploratory Endpoints 
The exploratory endpoints include the following: 
 mADCS-CGIC agitation score 
 Change from Baseline in NPI-C combined agitation and aggression domain scores 
 Change from Baseline in NPI-C individual agitation and aggression domain scores 
 Change from Baseline to Week 12 in the ADCS-ADL score 
 Change from Baseline to Week 12 in NPI-C total score 
 Change from Baseline to Week 12 in NPI-C sleep disorders domain score 
 Change from Baseline to Week 12 in NPI-C combined delusions and hallucinations 
domain scores 
 Change from Baseline to Week 12 in NPI-C combined dysphoria and 
apathy/indifference domain scores 
 Change from Baseline to Week 12 in individual NPI-C domain scores (other than 
agitation, aggression, and sleep disorders) 
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 Change from Baseline in CMAI subscale scores  
 Change from Baseline in KSS score  
 Change from Baseline in the MMSE score 
 The proportion of subjects taking any rescue medication  
The mADCS-CGIC agitation score at each timepoint will be summarized using an MMRM 
model with effects for treatment group (pimavanserin 34 mg, pimavanserin 20 mg, or 
placebo), visit (Weeks 2, 4, 8, and 12), the treatment-by-visit interaction, and geographic 
region (North America, Europe, or Rest of World). There is no baseline value to include in 
the model.  
The change from baseline to each post-baseline timepoint in the NPI-C combined agitation 
and aggression domain scores, NPI-C individual agitation and aggression domain scores, 
CMAI subscale scores, and KSS will be summarized using an MMRM model similar to that 
described above for the primary endpoint, except that the baseline value of the endpoint 
being summarized will be included in the model instead of the baseline CMAI total score. 
The change from baseline to Week 12 in the ADCS-ADL and NPI-C total score, combined 
delusions and hallucinations, combined dysphoria and apathy/indifference, and individual 
domain scores (except the agitation and aggression domains) will be summarized using an 
analysis of covariance (ANCOVA) model with effects for treatment group (pimavanserin 
34 mg, pimavanserin 20 mg, or placebo), and baseline value of the endpoint being 
summarized, and geographic region (North America, Europe, or Rest of World). 
The change from baseline to each post-baseline timepoint in the MMSE will be summarized 
using an MMRM model similar to that described above for the primary endpoint, except that 
the baseline value of the MMSE will be included in the model instead of the baseline CMAI 
total score. Also, the MMSE is not measured at Week 2. 
The proportion of subjects taking any rescue medication during the treatment period will be 
summarized by treatment group. 
9.7 
Responder Analyses 
Responder definitions for the CMAI total score, and for selected individual NPI-C domain 
scores, will be determined by examination of the cumulative distribution functions and by 
using anchor-based methods (e.g., anchoring to the mADCS-CGIC). Details will be provided 
in the SAP. 
In addition, a responder analysis based on the mADCS-CGIC will be performed, with 
response defined as moderate or marked improvement.  
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For each of these responder analyses, the proportion of responders will be summarized by 
treatment group at each timepoint using observed cases and also with missing values imputed 
as non-response.  
9.8 
Safety Analyses 
Safety results will be summarized by treatment group using descriptive statistics.  
9.8.1 
Adverse Events 
All AEs will be coded using the MedDRA coding dictionary. All AEs will be listed and 
TEAEs will be summarized by system organ class and preferred term. A TEAE is defined as 
an AE that started after the first dose of study drug. Summaries by maximum severity and by 
relationship will also be provided. Serious TEAEs, fatal TEAEs, and TEAEs leading to 
discontinuation will also be summarized.  
9.8.2 
Clinical Laboratory Values 
The serum clinical chemistry, hematology, and urinalysis results at baseline and at Weeks 4 
and 12 will be summarized by treatment group. Change from baseline values will also be 
summarized.  
The number and percentage of subjects with potentially clinically important post-baseline 
laboratory values will be summarized by treatment group at each post-baseline visit and 
overall post-baseline for selected parameters. The potentially clinically important criteria will 
be specified in the SAP. 
9.8.3 
Vital Signs and Body Weight  
Vital signs and body weight will be measured at baseline and each post-baseline visit will be 
summarized by treatment group. Change from baseline values will also be summarized. 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. 
9.8.4 
Electrocardiogram 
ECG parameters at baseline and at Weeks 4 and 12 will be summarized by treatment group. 
Change from baseline values will also be summarized. Categorical analyses will be 
conducted on the 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. 
9.8.5 
Physical Examinations 
The results of the physical examinations at each visit (Screening and Week 12 visit) will be 
tabulated by treatment group. 
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9.8.6 
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 clinician’s assessment 
will also be tabulated for each treatment group. 
9.9 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 
Plasma concentration data for pimavanserin and its active metabolite (AC-279) will be listed 
and summarized using descriptive statistics. Pimavanserin plasma concentration data will 
remain blinded until the unblinding of the clinical database at the end of the study. 
10 
REGULATORY COMPLIANCE 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH-GCP principles, and other applicable regulatory requirements. 
10.1 
Institutional Review Board 
The 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 
authorized representative [LAR] with subject’s assent) prior to initiating screening 
evaluations required by this protocol. Additionally, written agreement must be obtained from 
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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. If the subject is deemed not competent 
to provide informed consent for him/herself, 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 
accordance with local requirements and, if required, to the Regulatory Authority, as either an 
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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 post-randomization 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 
Åkerstedt T, Gillberg M. Subjective and Objective Sleepiness in the Active Individual. 
International Journal of Neuroscience. 1990; 52:1-2, 29-37. 
Amann B, Pantel J, Grunze H, et al. Anticonvulsants in the treatment of aggression in the 
demented elderly: an update. Clin Pract Epidemiol Ment Health. 2009;5:14. 
Ballard C, Thomas A, Gerry S, et al.; and MAIN-AD investigators. A double-blind 
randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for 
the long-term treatment of function and neuropsychiatric symptoms in people with 
Alzheimer's disease (MAIN-AD). J Am Med Dir Assoc. 2015;16(4):316-322. 
Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci. 
2006;7(6):492–500. 
Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for 
Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies. 
Silver Spring, MD: US Department of Health and Human Services; December 2012. 
Cohen-Mansfield J, Billig N. Agitated behaviors in the elderly. I. A conceptual review. J Am 
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13
APPENDICES 
Appendix A
Schedule of Events and Assessments.......................................................... 76
Appendix B
International Psychogeriatric Association (IPA) Guidelines ...................... 78
Appendix C
Prohibited and Restricted Concomitant Medications ................................. 79
Appendix D
List of Prohibited CYP3A4 Inhibitors and Inducers ................................... 82
Appendix E
Cohen-Mansfield Agitation Inventory (CMAI)  SAMPLE ...................... 83 
Appendix F
Zarit Burden Interview (ZBI)  SAMPLE .................................................. 87 
Appendix G
 Neuropsychiatric Inventory – Clinician Rating Scale (NPI-C) 
SAMPLE ..................................................................................................... 91
Appendix H
Mini-Mental State Examination (MMSE)  SAMPLE ............................ 109 
Appendix I
 Modified Alzheimer’s Disease Cooperative Study – Clinical Global
Impression of Change (mADCS-CGIC)  SAMPLE ...............................113 
Appendix J
Karolinska Sleepiness Scale (KSS)  SAMPLE.......................................120 
Appendix K
 Alzheimer’s Disease Cooperative Study-Activities of Daily Living
Inventory (ADCS-ADL)  SAMPLE .......................................................122 
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APPENDIX A 
SCHEDULE OF EVENTS AND ASSESSMENTS 
Procedure 
Screening 
Period 
Treatment Period 
Follow-Up 
Visit Number 
Visit 1a 
Baseline 
(1) 
Visit 2a 
Visit 3a 
Visit 4a 
Visit 5a 
(EOS/ET) 
Visit 6a 
Visit Week (Day) 
Week -2 to -4b 
Week 2 
(15) 
Week 4 
(29) 
Week 8 
(57) 
Week 12 
(85) 
Week 16c 
(~115) 
Allowable visit window (# days) 
NA 
NA 
3 
3 
3 
3 
+7 
Clinic (C) or Telephone (T) Visit 
C 
C 
C 
C 
C 
C 
T 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria assessment 
X 
Xd 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
Alzheimer’s disease history 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
 
Vital signs (including heighte and weight)  
X 
X 
X 
X 
X 
X 
 
ECGf 
X 
X 
 
X 
 
X 
 
Clinical laboratory testsg 
X 
X 
 
X 
 
X 
 
Pregnancy testh 
X 
X 
 
X 
 
X 
 
PK sampling 
 
X 
Xi 
X 
 
X 
 
CMAI 
 
X 
X 
X 
X 
X 
 
ZBI 
 
X 
X 
X 
X 
X 
 
NPI-C (Agitation and Aggression Domains)  
Xj 
X 
X 
X 
X 
X 
 
NPI-C (All Remaining Domains) 
 
X 
 
 
 
X 
 
MMSE 
X 
X 
 
X 
X 
X 
 
mADCS-CGIC 
 
X 
X 
X 
X 
X 
 
KSS 
 
X 
X 
X 
X 
X 
 
ADCS-ADL  
 
X 
 
 
 
X 
 
MRI or CTk 
X 
 
 
 
 
 
 
Psychosocial therapy 
X 
 
 
 
 
 
 
Assessment of concomitant medications/treatments 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse eventsl 
X 
X 
X 
X 
X 
X 
X 
GCAS 
X 
X 
X 
X 
X 
X 
X 
Randomization  
 
X 
 
 
 
 
 
Dispense study drug 
 
X 
 
X 
X 
 
 
Study drug administration at the clinicm 
 
X 
 
 
 
 
 
Study drug accountability 
 
 
 
X 
X 
X 
 
Abbreviations and footnotes on next page. 
 
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Abbreviations: AD=Alzheimer’s Disease; ADCS-ADL=Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory; C=clinic visit; 
CMAI=Cohen-Mansfield Agitation Inventory; CT=computed tomography; ECG=electrocardiogram; EOS=end of study; ET=early termination; GCAS=Global 
Clinician Assessment of Suicidality; KSS=Karolinska Sleepiness Scale; MMSE=Mini-Mental State Examination; mADCS-CGIC=modified Alzheimer’s Disease 
Cooperative Study – Clinical Global Impression of Change; MRI=magnetic resonance imaging; NA=not applicable; NPI-C=Neuropsychiatric Inventory-
Clinician Rating Scale; PK=pharmacokinetic; 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) calculated from the Baseline Visit 
(Day 1). Clinic visits may be split over multiple days within the specified windows, if necessary. 
b. 
The screening period must be at least 2 weeks long and no more than 4 weeks long. 
c. 
For subjects who discontinue prematurely from the study or who do not enroll in the open-label extension study, a follow-up safety assessment will be 
conducted by telephone call approximately 30 days after the last dose of study drug. 
d. 
NPI-C combined agitation and aggression domain score, ECG, and wash-out of prohibited medications are the only eligibility assessments  required at both 
Screening and Baseline (Day 1). All other eligibility criteria are to be established during Screening. 
e. 
Height is assessed as part of the vital sign measurement only at the Screening Visit; weight will be assessed at every clinic visit as part of the vital sign 
measurements. 
f. 
12-lead ECG to be completed in triplicate at screening and single read at subsequent visits. ECGs can be performed any time before blood sampling or at 
least 30 minutes after blood sampling during clinic visits. 
g. 
Urinalysis requirement not applicable to subjects who are unable to provide urine sample (e.g., incontinent subjects). 
h. 
A serum pregnancy test should be performed at the initial screening visit. A urine pregnancy test should be performed at Baseline (Day 1), Week 4, and 
Week 12 (EOS/ET) for female subjects of childbearing potential. 
i. 
Note: If collection at Week 2 does not occur, then collection should be attempted at Week 8.  
j. 
Only the agitation and aggression domain will be completed at the Screening Visit. 
k. 
MRI or CT must be obtained during or subsequent to diagnosis of probable AD, or during the screening period (prior to Baseline). 
l. 
Any untoward medical occurrence that occurs after signing the informed consent form (i.e., during the screening period) should be recorded as an adverse 
event, even if dosing has not begun. 
m. 
The first dose of study drug must be administered to the subject at the clinic only after all baseline assessments are performed, including the blood sampling 
for PK assessment. If any baseline assessments extend to an additional day, the first dose of study drug will be administered at completion of assessments on 
this day. 
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APPENDIX C 
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 and should be tapered 
off and discontinued at least 2 weeks prior to Baseline. These include, but are not 
limited to diphenhydramine, benztropine, biperiden, and trihexylphenidyl. 
○ 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 unchanged for at least 4 weeks prior to Baseline and should 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 must be unchanged for at least 4 weeks prior to Baseline and 
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 5.7.3. 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 
Prohibited at study entry but allowed in restricted situations after randomization 
○ Use of ciprofloxacin and azithromycin is prohibited at Baseline. However, use of 
these drugs during the course of the study to treat a bacterial infection (e.g., 
urinary tract infection, respiratory infection), post-Baseline may be permitted at 
the discretion of the PI. 
Restricted under certain conditions: 
○ Citalopram and escitalopram are restricted to a maximum dose of 20 mg a day. If 
it is clinically appropriate, subjects on a higher dose of citalopram or escitalopram 
should be titrated down to 20 mg a day prior to Baseline. 
○ 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 
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block [LBBB], an intraventricular conduction disturbance [IVCD], or 
ventricular pacing)  
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 D 
LIST OF PROHIBITED CYP3A4 INHIBITORS AND INDUCERS  
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/DrugInteractionsLabeling/uc
m093664.htm#classInhibit). 
 
 
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