Conditions: Neuropsychiatric Symptoms Related to Neurodegenerative Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 784
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and tolerability of pimavanserin compared to placebo in adult and elderly subjects with neuropsychiatric symptoms related to neurodegenerative disease.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Pimavanserin intervention 2: Placebo
Intervention descriptions: intervention 1: Pimavanserin 34 mg total daily dose, tablets, once daily by mouth (provided as two 17 mg NUPLAZID® tablets) intervention 2: Placebo, tablets, once daily by mouth (provided as two placebo tablets)

Protocol document:
Prot_000.pdf: 
Official Title: A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-
controlled, Safety Study of Pimavanserin Therapy in Adult and Elderly Subjects 
Experiencing Neuropsychiatric Symptoms Related to Neurodegenerative Disease 
NCT Number: NCT03575052 
Document Date: 5 March 2021 


 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 92 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Safety Study of Pimavanserin Therapy in Adult and Elderly Subjects With 
Neuropsychiatric Symptoms Related to Neurodegenerative Disease 
 
Protocol Number: ACP-103-046 
Amendment 7 
EudraCT Number: 2017-003536-36 
 
Original Protocol Date: 25 August 2017 
Protocol Amendment 1 Date: 4 October 2017 
Protocol Amendment 2 Date: 5 December 2017 
Protocol Amendment 3 Date: 30 January 2018 
Protocol Amendment 4 Date: 1 May 2018 
Protocol Amendment 5 Date: 9 January 2019 
Protocol Amendment 6 Date: 23 July 2019 
Protocol Amendment 7: 5 March 2021 
 
 
 
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. 


Study: ACP-103-046 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 7 
 
Date: 5 March 2021 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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SPONSOR SIGNATURE PAGE 
Title: A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-controlled, Safety Study 
of Pimavanserin Therapy in Adult and Elderly Subjects With Neuropsychiatric Symptoms 
Related to Neurodegenerative Disease   
 
 
Acadia Head of R&D: 
 
 
 
 
 
   
            See appended electronic signature page 
 
 
 
Acadia Study Lead: 
 
 
 
 
 
  
           See appended electronic signature page 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
Signature 
Date 


Signature Page for ACP-103-046 Protocol Amendment 7
Signature Page for ACP-103-046 Protocol Amendment 7
Approve
06-Mar-2021 03:46:19 GMT+0000
Approve
06-Mar-2021 04:10:39 GMT+0000


Study: ACP-103-046 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 7 
 
Date: 5 March 2021 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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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 Good Clinical Practice, as required by International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidelines E6 and as 
described in the United States (US) Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 
56, 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) 
 
 


Study: ACP-103-046 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 7 
 
Date: 5 March 2021 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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PROTOCOL SYNOPSIS 
Sponsor: Acadia Pharmaceuticals Inc. 
Name of Investigational Product: Pimavanserin 
Protocol Title: A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Safety Study of Pimavanserin Therapy in Adult and Elderly Subjects With Neuropsychiatric 
Symptoms Related to Neurodegenerative Disease   
Protocol Number: ACP-103-046 
EudraCT Number: 
2017-003536-36 
Phase: 3b 
Primary Objective 
• 
To assess the safety and tolerability of 
pimavanserin compared to placebo in 
adult and elderly subjects with 
neuropsychiatric symptoms related to 
neurodegenerative disease   
Primary Measure 
• 
Treatment-emergent adverse events 
(TEAEs) 
 
Secondary Objective 
• 
To assess the safety and tolerability of 
pimavanserin compared to placebo in 
adult and elderly subjects with 
neuropsychiatric symptoms related to 
neurodegenerative disease, as described 
by: 
o extrapyramidal symptoms 
o cognition 
Secondary Endpoints 
• 
Change from Baseline to Week 8 in 
Extrapyramidal Symptom Rating 
Scale-Abbreviated (ESRS-A) 
• 
Change from Baseline to Week 8 in 
Mini-Mental State Examination 
(MMSE) 
Exploratory Objectives 
• 
To assess the safety and tolerability of 
pimavanserin compared to placebo in 
adult and elderly subjects with 
neuropsychiatric symptoms related to 
neurodegenerative disease, as described 
by suicidality 
 
 
• 
To evaluate the benefit of pimavanserin 
compared with placebo in adult and 
elderly subjects with neuropsychiatric 
symptoms related to neurodegenerative 
disease 
 
Exploratory Endpoints 
Safety and tolerability of pimavanserin as 
described by: 
• 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) score or Global 
Clinician Assessment of Suicidality 
(GCAS) scale (if the subject is not 
able to complete the C-SSRS in the 
Investigator’s judgment) 
 
Benefit of pimavanserin as described by: 
• 
Change from Baseline to Week 8 in 
Clinical Global Impression-Severity 
(CGI-S) score for neuropsychiatric 
symptoms 


Study: ACP-103-046 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 7 
 
Date: 5 March 2021 
 
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• 
Clinical Global Impression-
Improvement (CGI-I) score at 
Week 8 for neuropsychiatric 
symptoms 
• 
Change from Baseline to Week 8 in 
5-level EuroQol-5D (EQ-5D-5L) 
score 
• 
Change from Baseline to Week 8 in 
sleep disturbances (assessed by 
Sleep Disorders Inventory [SDI]) 
 
Number of Study Sites 
Approximately 100 global sites will participate in this study. 
Number of Subjects 
Planned 
This study will screen approximately 1500 adult and elderly 
subjects to enroll approximately 750 subjects, allowing for a 50% 
screen failure rate. Approximately 375 subjects will be randomized 
to the pimavanserin group as well as the placebo group (i.e., 
375 subjects in each treatment group). With an assumed dropout 
rate of 30% in the double-blind phase, 525 subjects in total are 
expected to complete the study. 
Main Criteria for 
Inclusion and 
Exclusion 
To be eligible for this study, subjects must meet all of the inclusion 
criteria and none of the exclusion criteria. 
Inclusion Criteria: 
1. Is a male or female ≥60 years of age 
2. Can understand the nature of the trial and protocol 
requirements and provide written informed consent. 
If the subject is deemed not competent to provide informed 
consent, the following requirements for consent must be 
met: 
a. The subject’s legally acceptable representative 
(LAR) (or study partner/caregiver, if local 
regulations allow) must provide written informed 
consent 
b. The subject must provide written (if capable) 
informed assent 
3. Subject requires some or complete assistance with one or 
more of the following: 
a. Instrumental activities of daily living 
(communication, transportation, meal preparation, 
shopping, housework, managing medications, 
managing personal finances) OR 


Study: ACP-103-046 
 
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Date: 5 March 2021 
 
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b. Basic activities of daily living (personal hygiene, 
dressing, eating, maintaining continence or 
transferring) 
4. Meets clinical criteria for at least one of the following 
disorders, with or without cerebrovascular disease (CVD): 
a. Parkinson’s disease with or without dementia as 
defined by the Movement Disorder Society’s Task 
Force (Appendix B) 
b. Dementia with Lewy bodies (DLB) (Appendix C) 
c. All-cause dementia, possible or probable 
Alzheimer’s disease (AD) (Appendix A) 
d. Frontotemporal degeneration spectrum disorders, 
including possible or probable: 
i. Behavioral variant frontotemporal dementia 
(Appendix D) 
ii. Progressive supranuclear palsy  
(Appendix E) 
iii. Corticobasal degeneration (Appendix F) 
e. Vascular dementia, including post-stroke dementia, 
multi-infarct dementia and/or subcortical ischemic 
vascular dementia (SIVD) (Appendix G) 
5. Has an MMSE score ≥6 at Visit 1 (Screening) and Visit 2 
(Baseline) 
6. Has neuropsychiatric symptoms severe enough to warrant 
treatment with an antipsychotic agent, as evidenced by the 
Neuropsychiatric Inventory (NPI) score 
(Frequency×Severity) ≥4 on at least one of the following 
domains at Visit 1 (Screening) and Visit 2 (Baseline) (the 
domains at Screening and Baseline can be different): 
a. Domain A Delusions; OR 
b. Domain B Hallucinations; OR 
c. Domain D Depression/Dysphoria; OR 
d. Domain G Apathy/Indifference; OR 
e. Domain H Disinhibition; OR 
f. Domain I Irritability/Lability; OR 
g. Domain K Sleep  
7. Has a CGI-S score of ≥4 when assessing neuropsychiatric 
symptoms at Visit 1 (Screening) and Visit 2 (Baseline) 


Study: ACP-103-046 
 
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8. Has lived at the current place of residence for at least 
3 weeks prior to Visit 1 (Screening) and there are no plans 
to move to a different location 
9. Has a designated study partner/caregiver who meets the 
following requirements: 
a. In the Investigator’s opinion, is in contact with the 
subject frequently enough to accurately report on 
the subject’s symptoms and whether or not the 
subject is taking the study drug 
b. In the Investigator’s opinion, is considered reliable 
in providing support to the subject to help ensure 
compliance with study treatment, study visits, and 
protocol procedures 
c. Is fluent in the local language in which study 
assessments will be administered 
d. Agrees to participate in study assessments, has the 
capacity to provide informed consent, and provides 
written consent to participate in the study 
10. Can come to the clinic for study visits with a study 
partner/caregiver 
11. Has had a magnetic resonance imaging (MRI) or computed 
tomography (CT) scan of the brain within the last 3 years, 
and the scan or its final interpretation is available for 
review. If not available, a screening CT or MRI must be 
done during the screening period. 
12. If the subject is taking a cholinesterase inhibitor, 
memantine, or both: 
a. the dose of the medication(s) must be stable for at 
least 12 weeks prior to Visit 2 (Baseline) and there 
must be no current plan to change the dose; OR 
b. if the medication(s) was discontinued, the 
discontinuation must occur no fewer than 2 weeks 
prior to Visit 2 (Baseline)  
13. If the subject is taking an antipsychotic medication at the 
time of screening, the antipsychotic medication must be 
discontinued 2 weeks or 5 half-lives (whichever is longer) 
prior to Visit 2. 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 


Study: ACP-103-046 
 
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Date: 5 March 2021 
 
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not well-controlled or the subject cannot tolerate the current 
medication). 
14. If the subject is female, she must not be pregnant or 
breastfeeding. She must also 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 or be abstinent for at 
least 1 month prior to Visit 2 (Baseline), during the study, 
and 1 month following completion of the study. 
Abstinence as a method of contraception is defined as 
refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. This 
option is usually made for a specific moral, religious, legal, 
or health reason. If heterosexual intercourse does occur, an 
acceptable method of birth control is required. 
Acceptable methods of birth control include the following: 
• Condom, diaphragm, or cervical cap with 
spermicide 
• Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
• Intrauterine device (IUD) 
Exclusion Criteria: 
1. Is in hospice, is receiving end-of-life palliative care, or is 
bedridden 
2. Has neuropsychiatric symptoms that are primarily 
attributable to current delirium or substance abuse 
(i.e., neuropsychiatric symptoms not related to 
neurodegenerative disease)  
3. Has current evidence of an unstable neurological, 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical disorder, including cancer or 
malignancies that, in the judgment of the Investigator, 
would jeopardize the safe participation of the subject in the 
study or significantly interfere with the conduct or 
interpretation of the study 
4. Has a history of epilepsy   
5. Has atrial fibrillation unless adequately anticoagulated 


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Date: 5 March 2021 
 
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6. Has a history of myocardial infarction, unstable angina, 
acute coronary syndrome, or cerebrovascular accident 
within the last 6 months prior to Visit 1 (Screening) 
7. Has any of the following: 
a. greater than New York Heart Association (NYHA) 
Class 2 congestive heart failure (Appendix J) 
b. Grade 2 or greater angina pectoris (by Canadian 
Cardiovascular Society Angina Grading Scale) 
(Appendix K) 
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsades de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
8. Has a history of human immunodeficiency virus (HIV) or 
hepatitis C infection 
9. Has a history of neuroleptic malignant syndrome or 
serotonin syndrome 
10. Has a known personal or family history of long QT 
syndrome or family history of sudden cardiac death 
11. Has any of the following ECG results at Visit 1 (Screening) 
or Visit 2 (Baseline): 
a. If the subject is not on citalopram, escitalopram, or 
venlafaxine: 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or 
venlafaxine: 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 
At Screening, if the set of triplicate ECGs has a prolonged 
QTcF due to an identifiable cause, and it is medically 
appropriate to address that cause, a repeat set of triplicate 
ECGs may be performed during Screening at the discretion 
of the Medical Monitor.  
12. Has a heart rate <50 beats per minute. If bradycardia is 
secondary to iatrogenic or treatable causes and these causes 
are treated, a heart rate assessment can be repeated during 
the screening period.  


Study: ACP-103-046 
 
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13. Has a clinically significant CNS abnormality that is most 
likely contributing to the dementia or findings on MRI or 
CT including: 
a. intracranial mass lesion (including but not limited 
to meningioma [>1 cm3 with evidence of 
peritumoral edema] or glioma) 
b. vascular malformation 
c. intracranial aneurysm >4 points by PHASES score 
(Appendix L) 
d. evidence of >4 hemosiderin deposits (definite 
microhemorrhage or superficial siderosis) 
14. Has clinically significant neuroimaging or laboratory 
abnormalities during Screening that in the judgment of the 
Investigator would jeopardize the safe participation of the 
subject in the study. In consultation with the Medical 
Monitor, these subjects may be rescreened after appropriate 
treatment of their medical condition. 
15. Has major surgery planned during the screening through 
end of the treatment or follow-up periods 
16. Requires treatment with a medication or other substance 
that is prohibited by the protocol 
17. Has a body mass index (BMI) <18.5 kg/m2 or known 
unintentional clinically significant weight loss (i.e., ≥7%) 
over past 6 months 
18. The urine drug screen result at Visit 1 (Screening) indicates 
the presence of amphetamine/methamphetamine, 
barbiturates, cocaine, or phencyclidine (PCP). Subjects who 
test positive for amphetamines may be retested during 
Screening if they agree to abstain from the medication for 
the length of their participation in the study and if 
abstinence from medication usage is achieved at least 
7 days prior to Visit 2 (Baseline). The repeat Screening test 
must be negative for them to participate in the study. The 
presence of benzodiazepines, marijuana (THC), or opiates 
does not necessarily exclude the subject from the study. 
19. Is suicidal at Screening or Baseline as defined below: 
a. If the subject can complete the Columbia-Suicide 
Severity Rating Scale (C-SSRS), he or she must not 
be actively suicidal at Visit 1 (Screening) or Visit 2 
(Baseline) (including, an answer of “yes” to 


Study: ACP-103-046 
 
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C-SSRS questions 4 or 5 [current or over the last 
6 months]) and must not have attempted suicide in 
the 2 years prior to Visit 1 (Screening); OR 
b. If the subject is not able to reliably complete the 
C-SSRS in the Investigator’s judgment, the subject 
must not be suicidal as assessed by the Global 
Clinician Assessment of Suicidality (GCAS) score 
(i.e., a score of 3 or 4) based on Investigator’s 
assessment of behavior within the 3 months prior to 
Visit 1 (Screening) or since-last-visit at Visit 2 
(Baseline); OR 
c. The subject is actively suicidal in the Investigator’s 
judgment 
20. Has participated in or is participating in a clinical trial of 
any investigational drug, device, or intervention, within 
30 days or 5 half-lives, whichever is longer, of Visit 2 
(Baseline) 
21. Has previously been enrolled in any prior clinical study 
with pimavanserin or is currently taking pimavanserin 
22. Has a significant sensitivity or allergic reaction to 
pimavanserin or its excipients 
23. Is an employee or is a family member of an employee of 
Acadia Pharmaceuticals Inc. 
24. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study for any reason, including if the 
subject is judged to be a danger to self or others 
Test Product, Dose, and 
Administration 
Pimavanserin 34 mg (provided as 2×17 mg tablets) or matching 
placebo (2×placebo tablets [size- and color-matched to 
pimavanserin]) 
Planned Duration of 
Treatment 
The duration of participation for individual study subjects will be 
up to 16 weeks, consisting of a screening period of up to 4 weeks, 
an 8-week double-blind treatment period, and a safety follow-up 
period of 30 (+4) days (for those subjects who discontinue 
prematurely from the study or who do not enroll in the open-label 
extension study) (Figure S–1). The end of the clinical study will be 
when the last subject completes the last scheduled assessment. If 
the study is terminated for any reason, subjects remaining in the 
study will return to standard of care. 
Study Design 
This study will be conducted as a multicenter, randomized, 
double-blind, placebo-controlled, parallel-group study in adult and 
elderly subjects with neuropsychiatric symptoms related to 


Study: ACP-103-046 
 
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neurodegenerative disease. 
The study will have 3 periods: 
• 
Screening period (3-28 days) 
• 
Double-blind treatment period (8 weeks) 
• 
Safety follow-up period (30 [+4] days) 
Screening Period (3-28 Days) 
During the screening period, adult and elderly subjects will be 
assessed for study eligibility and prohibited medications will be 
discontinued. Investigators should not withdraw a subject’s 
prohibited medication for the purpose of enrolling them into the 
study. Medications should be discontinued only if it is deemed 
clinically appropriate to do so and in consultation with the treating 
physician. 
Double-blind Period (8 Weeks) 
The Baseline visit (Visit 2) may occur as soon as screening 
procedures are completed and subject eligibility has been 
confirmed. At Visit 2, subjects will be randomized in a 1:1 ratio to 
pimavanserin 34 mg once daily (QD) or matching placebo. It is 
recommended that the subject take the study drug at approximately 
the same time each day. Assessments will be conducted at Week 0 
(Baseline), 1, 2, 4, 6, and 8/early termination (ET). 
Safety Follow-up Period (30 Days) 
Eligible subjects who successfully complete the 8-week 
double-blind period will be eligible to enroll in an open-label 
extension study. For subjects who discontinue prematurely from 
the study or who do not enroll in the open-label extension study, 
a follow-up safety assessment visit should be conducted 30 (+4) 
days after the last dose of study drug. 
The schedule of assessments is provided in Table S–1. 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board will review 
safety information on a regular basis throughout the study. 
Sample Size 
Calculations 
A sample size of 375 adult and elderly subjects in each treatment 
group ensures that within each treatment group, the probability of 
observing at least 1 adverse event (AE) with a true incidence of 
1.0% is 0.977; the probability of observing at least 1 AE with a 
true incidence of 1.5% is 0.997; and the probability of observing at 
least 1 AE with a true incidence of 2.0% is 0.999. 


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Statistical Methods 
Analysis Sets 
The primary analyses will be based on the Safety Analysis Set. 
The Safety Analysis Set is defined as all subjects who take at least 
1 dose of study drug. 
Primary 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. All AEs will be listed and treatment-emergent adverse 
events (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 and no later than 30 days after the last 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.  
Secondary Analyses 
MMSE and ESRS-A observed values and change from Baseline 
will be summarized by treatment group and visit. The change from 
Baseline in the MMSE and ESRS-A scores will be summarized 
using mixed model repeated measures (MMRM). The model will 
include effects for region, treatment group, visit, treatment-by-visit 
interaction, Baseline score, and Baseline score-by-visit interaction. 
No formal comparisons between treatment groups are planned. 
The MMRM results for the pimavanserin and placebo groups will 
be tabulated by visit. 
Exploratory Analyses 
For the C-SSRS, the number and percentage of subjects with 
suicidal ideation or suicidal behavior during the study will be 
tabulated. For the GCAS, the number and percentage of subjects 
with a score of 3 or 4 during the study will be tabulated. 
The CGI-I scores and the change from Baseline in the CGI-S and 
SDI scores will be summarized using MMRM. The model will 
include effects for region, treatment group, visit, treatment-by-visit 
interaction, Baseline score, and Baseline score-by-visit interaction. 
For CGI-I, the Baseline CGI-S score will be used as the Baseline 
covariate in the model. The change from Baseline in the 
EQ-5D-5L will be summarized using an ANCOVA model with 
effects for region, treatment group, and Baseline score. No formal 
comparisons between treatment groups are planned. The MMRM 


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results for the pimavanserin and placebo groups will be tabulated 
by visit. 
Other Safety Analyses 
The serum clinical chemistry, hematology, and urinalysis results at 
each time point will be summarized by treatment group. Change 
from Baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically 
important (PCI) post-Baseline laboratory values will be 
summarized by treatment group at each post-Baseline visit and 
overall post-Baseline for selected parameters. The PCI criteria will 
be specified in the statistical analysis plan. 
Vital signs and body weight at Baseline and each post-Baseline 
visit will be summarized by treatment group. Change from 
Baseline values will also be summarized. 
The results of the physical examinations at each visit will be 
tabulated by treatment group. 
Electrocardiogram parameters at study visits 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. 
Date 
5 March 2021 
 


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Figure S–1 
Schematic of Study Design for ACP-103-046 
 
 
Abbreviation: R=randomization 
Note: Subjects who enroll in an open-label extension will not complete the Safety Follow-up Period. 
 


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Table S–1 
Schedule of Events and Assessments for ACP-103-046 
Period Screening 
Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Unscheduled 
Visit 
Week 
12 
Visit Number 
1 
2 
3 
4 
5 
6 
(EOT/ET) 
7 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
Psychiatric, dementia, and 
neurological history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
X 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
12-lead ECGb 
X 
X 
 
X 
 
 
X 
 
 
Clinical laboratory testsc 
X 
X 
 
 
X 
 
X 
 
 
Pregnancy testd 
X 
X 
 
 
 
 
X 
 
 
Urine drug screen 
X 
 
 
 
X 
 
X 
 
 
MMSE 
X 
X 
X 
X 
X 
X 
X 
 
 
NPI  
X 
X 
 
 
 
 
 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
 
 
C-SSRSe or GCASe 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESRS-A 
 
X 
X 
X 
X 
X 
X 
X 
 
Table abbreviations and footnotes on next pages. 
 


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Table S–1 
Schedule of Events and Assessments for ACP-103-046 (Continued) 
Period Screening 
Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Unscheduled 
Visit 
Week 
12 
Visit Number 
1 
2 
3 
4 
5 
6 
(EOT/ET) 
7 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
EQ-5D-5L 
 
X 
 
 
 
 
X 
 
 
SDI 
 
X 
 
 
X 
 
X 
 
 
CT/MRIf 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispense study drug 
 
X 
 
X 
X 
X 
 
X 
 
Study drug accountability 
 
 
 
X 
X 
X 
X 
X 
 
Abbreviations: CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-Severity; CRF=case report form; C-SSRS=Columbia-
Suicide Severity Rating Scale; CT=computed tomography; ECG=electrocardiogram; EOT=end of treatment; EQ-5D-5L=5-level EuroQol-5D; 
ESRS-A=Extrapyramidal Symptom Rating Scale-Abbreviated; ET=early termination; GCAS=Global Clinician Assessment of Suicidality; MMSE=Mini–
Mental State Examination; MRI=magnetic resonance imaging; NPI=Neuropsychiatric Inventory; SDI=Sleep Disorders Inventory 
a 
This visit is a safety follow-up telephone call visit for subjects who discontinue prematurely from the study or who do not participate in the long-term 
extension study. This visit will occur 30 (+4) days after the last dose of study drug. 
b 
At Visit 1, ECG should be completed in triplicate. At all other visits, a single 12-lead ECG should be completed. These should occur before blood sampling 
or at least 30 minutes after blood sampling. 
c 
To include hematology, serum chemistry, prolactin levels, and urinalysis. Urinalysis requirement is not applicable to subjects who are unable to provide 
urine sample (e.g., incontinent subjects). Where collection of a urine sample proves impractical or impossible, failure to collect a urine sample should be 
recorded in the subject’s CRF, and will not be considered a protocol deviation. 
d 
A pregnancy test is only required for women of childbearing potential. Serum pregnancy should only be performed at Visit 1; a urine pregnancy test should 
be performed at all subsequent visits. If urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be done in its place.  
e 
Suicidal assessment is required. For subjects who are able to complete the assessment, the Baseline/Screening version of the C-SSRS will be administered at 
Screening, and the Since Last Visit version of the C-SSRS will be administered at all subsequent visits. The C-SSRS is preferred. If the subject is not able to 
complete the C-SSRS in the Investigator’s judgment, the GCAS should be administered and used thereafter in the study. 
f 
A CT or MRI should only be completed if a CT or MRI scan has not been performed in the last 3 years prior to screening.


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR .................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 19 
LIST OF TABLES ................................................................................................................... 23 
LIST OF FIGURES ................................................................................................................. 23 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 24 
1 
INTRODUCTION ...................................................................................................... 26 
1.1 
Background Information ............................................................................................ 26 
1.2 
Investigational Product ............................................................................................... 28 
1.3 
Previous Clinical Experience ..................................................................................... 28 
1.3.1 
Parkinson’s Disease Psychosis Program .................................................................... 29 
1.3.2 
Alzheimer’s Disease Psychosis .................................................................................. 30 
1.4 
Study Rationale .......................................................................................................... 32 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 32 
2.1 
Primary Objective ....................................................................................................... 32 
2.1.1 
Primary Measure ........................................................................................................ 33 
2.2 
Secondary Objective ................................................................................................... 33 
2.2.1 
Secondary Endpoints .................................................................................................. 33 
2.3 
Exploratory Objective ................................................................................................ 33 
2.3.1 
Exploratory Endpoints ................................................................................................ 33 
3 
STUDY DESCRIPTION ............................................................................................ 34 
3.1 
Overview of Study Design ......................................................................................... 34 
3.2 
Screening Period (3-28 Days) .................................................................................... 34 
3.3 
Double-blind Period (8 Weeks) .................................................................................. 34 
3.4 
Safety Follow-up Period (30 Days) ............................................................................ 34 
4 
SUBJECT ELIGIBILTY AND WITHDRAWAL CRITERIA .................................... 35 
4.1 
Subject Selection and Withdrawal .............................................................................. 35 
4.2 
Inclusion Criteria ........................................................................................................ 35 
4.3 
Exclusion Criteria ....................................................................................................... 37 
4.4 
Subject Withdrawal or Termination ............................................................................ 40 


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4.5 
Prior and Concomitant Therapy ................................................................................. 41 
4.5.1 
Prior Medications ....................................................................................................... 41 
4.5.2 
Concomitant Medications ........................................................................................... 42 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 43 
5.1 
Investigational Product Description ........................................................................... 43 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 43 
5.1.2 
Product Storage and Stability ..................................................................................... 43 
5.1.3 
Dosing and Administration ......................................................................................... 43 
5.1.4 
Method of Assigning Subjects to Treatment Groups .................................................. 44 
5.1.5 
Blinding ...................................................................................................................... 44 
5.1.6 
Study Drug Compliance ............................................................................................. 44 
5.1.7 
Overdose ..................................................................................................................... 44 
5.2 
Investigational Product Accountability Procedures .................................................... 44 
6 
STUDY PROCEDURES ............................................................................................ 45 
6.1 
Screening Assessments ............................................................................................... 45 
6.1.1 
Neuropsychiatric Inventory ........................................................................................ 45 
6.1.2 
Mini-Mental State Examination ................................................................................. 45 
6.1.3 
Medical History and Demographics ........................................................................... 45 
6.1.4 
Psychiatric History ..................................................................................................... 46 
6.1.5 
Dementia History........................................................................................................ 46 
6.1.6 
Neurological History .................................................................................................. 46 
6.1.7 
Computed Tomography/Magnetic Resonance Imaging ............................................. 46 
6.2 
Exploratory Efficacy Assessments ............................................................................. 46 
6.2.1 
Clinical Global Impression – Severity and Improvement Scales ............................... 46 
6.2.2 
EQ-5D-5L ................................................................................................................... 46 
6.2.3 
Sleep Disorders Inventory .......................................................................................... 47 
6.3 
Safety Assessments ..................................................................................................... 47 
6.3.1 
Physical Examinations................................................................................................ 47 
6.3.2 
Vital Signs .................................................................................................................. 47 
6.3.3 
Height, Weight, and Body Mass Index ....................................................................... 47 
6.3.4 
Electrocardiograms ..................................................................................................... 47 
6.3.5 
Columbia-Suicide Severity Rating Scale ................................................................... 48 
6.3.6 
Global Clinician Assessment of Suicidality ............................................................... 48 


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6.3.7 
Extrapyramidal Symptom Rating Scale-Abbreviated ................................................ 49 
6.3.8 
Laboratory Evaluations .............................................................................................. 49 
6.4 
Safety Follow-up ........................................................................................................ 51 
6.5 
Unscheduled Visits ..................................................................................................... 52 
7 
ADVERSE EVENTS ................................................................................................. 52 
7.1 
Specification of Safety Parameters ............................................................................. 52 
7.1.1 
Definition of Adverse Event ....................................................................................... 52 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 53 
7.2 
Classification of an Adverse Event............................................................................. 54 
7.2.1 
Severity of Event ........................................................................................................ 54 
7.2.2 
Relationship to Study Drug ........................................................................................ 54 
7.2.3 
Definition of Unexpectedness .................................................................................... 56 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ............................ 56 
7.4 
Reporting Procedures ................................................................................................. 56 
7.4.1 
Adverse Event Reporting ........................................................................................... 56 
7.4.2 
Serious Adverse Event Reporting ............................................................................... 57 
7.4.3 
Reporting of Pregnancy .............................................................................................. 57 
7.4.4 
Reporting of Overdose ............................................................................................... 58 
8 
CLINICAL MONITORING ....................................................................................... 58 
9 
STATISTICAL METHODS AND DATA ANALYSIS ............................................... 58 
9.1 
Statistical and Analytical Plans .................................................................................. 58 
9.2 
Statistical Hypotheses ................................................................................................. 58 
9.3 
Sample Size Determination ........................................................................................ 58 
9.4 
Subject Populations for Analysis ................................................................................ 59 
9.5 
Description of Statistical Methods ............................................................................. 59 
9.5.1 
Primary Analyses ........................................................................................................ 59 
9.5.2 
Secondary Analyses .................................................................................................... 59 
9.5.3 
Exploratory Analyses.................................................................................................. 59 
9.5.4 
Other Safety Analyses ................................................................................................ 60 
9.5.5 
Interim Analyses ......................................................................................................... 60 
9.6 
Data and Safety Monitoring Board ............................................................................. 60 
9.7 
Measures to Minimize Bias ........................................................................................ 60 
9.8 
Breaking the Study Blind/Subject Code ..................................................................... 61 


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10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 61 
10.1 
Data Collection and Management Responsibilities .................................................... 61 
10.2 
Source Documents ...................................................................................................... 62 
10.3 
Case Report Forms ..................................................................................................... 62 
10.4 
Confidentiality ............................................................................................................ 62 
10.5 
Study Records Retention ............................................................................................ 62 
10.6 
Protocol Exceptions and Deviations ........................................................................... 63 
10.7 
Protocol Amendments ................................................................................................ 63 
11 
Quality Management .................................................................................................. 63 
11.1 
Risk Management ....................................................................................................... 63 
11.2 
Quality Control and Quality Assurance ...................................................................... 64 
12 
ETHICAL CONSIDERATIONS ................................................................................ 65 
12.1 
Ethical Standard.......................................................................................................... 65 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 65 
12.3 
Informed Consent Process .......................................................................................... 65 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 66 
12.3.2 Consent Procedures and Documentation .................................................................... 66 
13 
PUBLICATION PLAN .............................................................................................. 66 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 66 
14.1 
Finance, Insurance, and Indemnity ............................................................................. 66 
15 
LITERATURE REFERENCES .................................................................................. 67 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-103-046 .................................. 17 
Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer's 
Disease, Parkinson's Disease Dementia, and Dementia With Lewy Bodies ... 27 
Table 1–2 
NPI-NH Psychosis Score Percent Responder Analysis – Full Analysis Set 
– Week 6 (Day 43) ........................................................................................... 31 
Table 6–1 
Safety Laboratory Evaluations ......................................................................... 51 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-046 ................................................. 16 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AD 
Alzheimer’s disease 
ADP 
Alzheimer’s disease psychosis 
AE 
adverse event 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
CVD 
cerebrovascular disease 
DLB 
dementia with Lewy bodies 
DSMB 
Data and Safety Monitoring Board 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
EQ-5D-5L 
5-level EuroQol-5D 
ESRS-A 
Extrapyramidal Symptom Rating Scale-Abbreviated 
ET 
early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FTD 
frontotemporal dementia 
GCP 
Good Clinical Practice 
GCAS  
Global Clinician Assessment of Suicidality scale 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
LAR 
legally acceptable representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 


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Term 
Definition 
NPI 
Neuropsychiatric Inventory 
PDP 
Parkinson’s disease psychosis 
QD 
once daily 
QRS interval  
QRS interval of ECG 
QT interval  
QT interval for heart rate of ECG 
QTcB 
corrected QT interval using Bazett’s correction method 
QTcF 
corrected QT interval using Fridericia’s correction method 
SAE 
serious adverse event 
SDI 
Sleep Disorders Inventory  
SE 
standard error 
TEAE 
treatment emergent adverse event 
US 
United States 
VASCOG 
International Society for Vascular Behavioral and Cognitive 
Disorders 


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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol and the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline.  
1.1 
Background Information 
Neuropsychiatric symptoms, including behavioral symptoms, such as hallucinations, 
delusions, irritability, apathy and agitation, are common in patients with neurodegenerative 
disease. Almost all individuals with dementia exhibit neuropsychiatric symptoms over the 
course of the disease (Steinberg et al. 2008; Lanctot et al. 2017), causing distress for the 
patient and their caregivers, as they are “associated with impairment in activities of daily 
living, poor quality of life, earlier institutionalization, accelerated disease progression, 
increased mortality, caregiver stress, and increased cost of care” (Lanctot et al. 2017). 
Psychosis, apathy, agitation, depression and sleep disturbances are common neuropsychiatric 
symptoms associated with Alzheimer’s disease. The emergence of neuropsychiatric 
symptoms typically occurs in three phases: “(1) irritability, depression, and nighttime 
behavior changes; (2) anxiety, appetite changes, agitation, and apathy; and (3) elation, motor 
disturbances, hallucinations, delusions, and disinhibition” (Masters et al. 2015). 
Psychosis is a common neuropsychiatric symptom, particularly in patients with dementia 
associated with neurodegenerative disease. Psychotic symptoms are typical of dementia with 
Lewy bodies (DLB), very common in Alzheimer’s disease (AD) and occur, although to a 
lesser degree, in vascular dementia (VaD) and frontotemporal dementia (FTD) (Table 1–1). 
In one study, 67% of patients with dementia had psychotic symptoms (Ballard et al. 1995). It 
is also a frequent complication of Parkinson’s disease patients, with or without dementia. The 
psychosis in neurodegenerative diseases is typically dominated by visual hallucinations, with 
delusions often consisting of the reactions or rationalizations that follow. However, delusions 
do occur as distinct phenomena, often taking the form of misinterpretations of real or 
imaginary objects, delusions of infidelity or abandonment, or beliefs such as thinking that 
spouses or relatives are duplicates of the original person. Among AD patients, delusions are 
more common than hallucinations (Fischer et al. 2016; Ballard et al. 1995) while 
hallucinations are more common in patients with DLB and Parkinson’s disease dementia. 
Patients with psychosis who had a clinical diagnosis of AD are often found on autopsy to 
have Lewy bodies or vascular lesions (Fischer et al. 2016; Kim et al. 2017). 
 
 


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Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer's 
Disease, Parkinson's Disease Dementia, and Dementia With Lewy Bodies 
Dementia—prevalence 
Delusions 
60% 
Hallucinations 
20% 
Alzheimer's Disease—prevalence 
Delusions 
36% 
Hallucinations 
18% 
Parkinson's Disease —prevalence 
Hallucinations 
42% 
 
Visual hallucinations 
15.8-50% 
Delusions 
21% 
Dementia with Lewy Bodies—prevalence 
Hallucinations 
13-92% 
Paranoid delusions 
25-28.6% 
Source: Adapted from Jellinger (2012) 
There is evidence that psychotic features in Parkinson’s disease, AD, and DLB are associated 
with polymorphisms in the serotonergic pathway genes, in particular the 5HTTLPR 
polymorphism in SLA6A4, which codes for the serotonin transporter (Sweet et al. 2001; 
Quaranta et al. 2009; DeMichele-Sweet et al. 2010; Creese et al. 2014). This observation 
raises the possibility that there is a common biological link among those dementia patients 
who have psychotic features, regardless of subtype, and provides mechanistic support for the 
finding that pimavanserin, a compound with serotonergic but not dopaminergic activity, can 
have an effect on delusions and hallucinations. 
Treatment of neuropsychiatric symptoms associated with neurodegenerative disease 
represents an area of high unmet need. There are no approved therapies for psychosis 
associated with DLB or AD. A substantial number of these patients receive off-label 
antipsychotic drug treatment to control their symptoms. However, many of these drugs have 
not demonstrated efficacy in controlled trials, worsen patients’ motor symptoms, require 
extensive monitoring, or have other safety concerns. The lack of target engagement in a 
degenerating brain may limit the effectiveness of currently approved treatments, such as 
antidepressants and antipsychotics, for mood and psychotic symptoms (Lanctot et al. 2017). 
The CATIE-AD study concluded that the adverse effects of risperidone, olanzapine, and 
quetiapine limited their overall effectiveness (Schneider et al. 2006). 
Limited options are available for the treatment of neuropsychiatric symptoms in 
neurodegenerative disease. While atypical antipsychotics are sometimes used in clinical 
practice, none are approved in the United States (US) for this use, with the exception of 
pimavanserin which is approved for the treatment of hallucinations and delusions associated 


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with Parkinson’s disease psychosis (PDP). In Europe, atypical antipsychotics are generally 
not approved in this population based on their equivocal efficacy and poor benefit-risk 
assessment, particularly in elderly patients with dementia. In severe cases, limited indications 
exist for some antipsychotics; however, they are restricted to short-term treatment in patients 
with severe and persistent symptoms when non-pharmacological treatments have failed, and 
when there is risk of harm to self or others. For example, risperidone is approved in Canada 
and Europe for short-term treatment of persistent aggression in moderate to severe 
Alzheimer’s disease unresponsive to non-pharmacological approaches and when there is a 
risk of harm to self or others.  
Robust efficacy with pimavanserin was demonstrated without worsening the motor 
symptoms of Parkinson’s disease. In addition, a recently completed Phase 2 study 
(ACP-103-019) in AD psychosis (ADP) reported statistical superiority of pimavanserin over 
placebo on the primary efficacy endpoint of improvement in psychotic symptoms at Week 6 
of treatment (Ballard et al. 2018). With its highly targeted and selective receptor binding 
profile, pimavanserin represents a new pharmacologic paradigm to treat psychotic symptoms 
across neurodegenerative diseases. 
1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product as 
pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-
methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-
dihydroxybutanedioate (2:1). In April 2016, pimavanserin was approved in the US for the 
treatment of hallucinations and delusions associated PDP. 
Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 5-hydroxytryptamine (5HT [serotonin]) 2A (5-HT2A) 
receptor. At higher doses pimavanserin may block 5HT2C receptors (Vanover et al. 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 have benefits with regard to overall tolerability 
relative to other antipsychotic agents. 
1.3 
Previous Clinical Experience 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP. Studies have also been conducted in ADP and 


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schizophrenia. The PDP program and Phase 2 ADP studies are reviewed below. A more 
complete discussion of these studies, as well as the schizophrenia program, is available in the 
Investigator’s brochure. 
1.3.1 
Parkinson’s Disease Psychosis Program 
The scope of the development program for pimavanserin is the largest ever conducted in 
PDP. At the time of approval, 616 mostly older, late-stage PDP subjects had been evaluated in 
16 countries over a span of >10 years. Clinically meaningful efficacy was established in 
Study ACP-103-020, a 6-week, placebo-controlled Phase 3 study (Cummings et al. 2014). 
This efficacy was supported by data from additional short-term Phase 2b/3 studies. In Study 
ACP-103-020, pimavanserin 34 mg consistently demonstrated statistically significant 
efficacy across multiple and independent endpoints, subject subgroups, and sensitivity 
analyses. Improvements in sleep and daytime wakefulness were also observed. These clinical 
benefits were achieved without worsening of Parkinson’s disease motor symptoms and 
without a number of other safety concerns associated with atypical antipsychotics. 
Pimavanserin is considered to be generally safe and well tolerated. Across all clinical studies 
of pimavanserin, the most frequently reported treatment-emergent adverse events (TEAEs) 
were in the central nervous system (CNS), gastrointestinal, and psychiatric systems. Most 
events were mild to moderate in intensity. The most common CNS TEAEs included dizziness 
(including postural), headache, and somnolence (drowsiness). Common gastrointestinal 
disturbances included dyspepsia, nausea, constipation, and vomiting. Severe nausea and 
vomiting were dose limiting in a few cases. Reported psychiatric conditions included 
agitation, insomnia, and confusional state. 
Clinical and nonclinical 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. In the Phase 3 PDP 
program, an average prolongation of approximately 5 to 8 ms was observed with 
pimavanserin 34 mg. 
The US package insert for pimavanserin has a boxed warning that elderly patients with 
dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. 
Pimavanserin is not approved in the treatment of patients with dementia-related psychosis 
unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis. 
Additional information is provided in the pimavanserin Investigator’s brochure and in the 
NUPLAZID® (pimavanserin) US package insert. 


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1.3.2 
Alzheimer’s Disease Psychosis 
Evidence from the recently completed Phase 2 study (ACP-103-019) suggests that 
pimavanserin is effective in reducing hallucinations and delusions in patients with psychosis 
in Alzheimer’s disease (Ballard et al. 2018). 
Study ACP-103-019 was a Phase 2, 12-week, randomized, double-blind, placebo-controlled, 
single-center study to assess the safety and efficacy of pimavanserin 34 mg once daily in 
nursing home subjects with ADP. Eligible subjects were required to have a score of 4 or 
greater on either the hallucinations or delusions scale of the Neuropsychiatric 
Inventory-Nursing Home Version (NPI-NH) or a total combined Hallucinations and 
Delusions score of 6 or greater. The primary efficacy endpoint was change from Baseline to 
Day 43 in the NPI-NH psychosis score (Delusions+Hallucinations domains). 
A total of 181 subjects were randomized (n=90 pimavanserin and n=91 placebo) with 
178 subjects included in the Full Analysis Set (FAS; n=87 pimavanserin and n=91 placebo). 
The mean (standard error [SE]) age of subjects was 85.9 (0.48) years. The mean (SE) 
Baseline NPI-NH psychosis score for all FAS subjects was 9.8 (0.39) with comparable mean 
scores in the pimavanserin (9.5) and placebo (10.0) groups. The mean (SE) Mini-Mental 
State Examination (MMSE) score for all FAS subjects was 10.1 (0.40). 
Efficacy results for the primary endpoint (NPI-NH psychosis score after 6 weeks of treatment 
[Day 43] demonstrated a significant (p=0.0451; effect size [Cohen’s d]= -0.320) treatment 
effect for pimavanserin compared with placebo. Prespecified subgroup analyses supported a 
clinically relevant treatment effect in the pimavanserin group, as a larger effect size was 
generally observed in subjects with more severe psychosis. Similarly, the proportion of 
responders (subjects with 30% and 50% reductions from Baseline) was statistically 
significantly greater in the pimavanserin group compared to placebo (Table 1–2). On the 
endpoint of mean change in NPI-NH psychosis score at Week 12, pimavanserin achieved 
improvement to Week 12 but the difference from placebo was not maintained due to an 
observed improvement in the mean score in the placebo group between Weeks 6 and 12. 


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Table 1–2 
NPI-NH Psychosis Score Percent Responder Analysis – Full 
Analysis Set – Week 6 (Day 43) 
 
Percent Improvement from Baseline 
Treatment Group 
(% Responder) 
≥20% 
≥30% 
≥50% 
≥75% 
100% 
 
Pimavanserin 34 mg 
58.6% 
55.2% 
50.6% 
27.6% 
12.6% 
 
Placebo 
46.2% 
37.4% 
34.1% 
16.5% 
9.9% 
p-value for test of group difference 
0.0937 
0.0159 
0.0240 
0.0656 
0.5514 
Source: ACP-103-019 Clinical Study Report 
Note: Missing values were imputed as nonresponders 
With respect to secondary and exploratory endpoints, changes in individual domains of the 
NPI-NH were explored. A greater improvement in the NPI-NH Irritability/Lability 
(Domain I) score was observed on Day 43 in the pimavanserin group compared with placebo. 
No statistical separation was observed between treatment groups with respect to any of the 
other NPI-NH individual domain endpoints. However, individual domain score 
improvements were generally greater in the pimavanserin group than the placebo group, with 
the exception of NPI-NH Elation/Euphoria (Domain F) and NPI-NH Appetite and Eating 
Changes (Domain L). 
With respect to safety, pimavanserin once-daily appeared to be well-tolerated with no new 
safety observations in this elderly and frail patient population compared to the pimavanserin 
PDP safety database. An equal number of post-randomization deaths were reported: 4 deaths 
in the pimavanserin group and 4 in the placebo group. 
There were more serious adverse events (SAEs) reported in pimavanserin group (16.7%) than 
in the placebo group (11.0%). A review of the reported SAEs, both in the placebo and 
pimavanserin groups, did not reveal the presence of any common, underlying 
pathophysiologic mechanism or cause. However, there were fewer discontinuations due to 
TEAEs in the pimavanserin group (8.9%) compared with the placebo group (12.1%). 
The most common TEAEs in the pimavanserin group were fall (23.3%), urinary tract 
infection (22.2%), and agitation (21.1%), which have been described as associated with this 
elderly frail patient population. Of these, agitation was reported more often in the 
pimavanserin group than in the placebo group. 
The mean change from Baseline in the QTc interval in subjects treated with pimavanserin 
was 9.4 ms at 12 weeks (Day 85) with no significant outliers reported at Day 85 (>500 ms or 
delta ≥60 ms). One subject in the pimavanserin group and one subject in the placebo group 
had a delta ≥60 ms at Day 15. Each subject continued in the study. 


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Weight data was available for about half of the study participants at Day 85. Mean body 
weight and body mass index (BMI) remained relatively unchanged from Baseline to Day 85 
in both treatment groups. Overall, 1 (1.8%) subject in the placebo group and 7 (14.6%) 
subjects in the pimavanserin group experienced weight decrease of ≥7% and 5 (8.8%) 
subjects in the placebo group and 4 (8.3%) subjects in the pimavanserin group experienced 
weight increase of ≥7%. 
Changes from baseline in MMSE were similar in placebo and pimavanserin group indicating 
that pimavanserin did not affect cognitive function in these patients. Similarly, treatment with 
pimavanserin had no negative effect on motor function as measured by UPDRS Part III 
scores. 
1.4 
Study Rationale 
Pimavanserin is the only atypical antipsychotic approved in the US for the treatment of 
hallucinations and delusions associated with PDP. The safety database supporting the PDP 
development program consisted of >1200 patients and healthy subjects, including >600 PDP 
patients, representing the largest development program in PDP ever conducted. Pimavanserin 
has demonstrated a substantial improvement on measures of psychotic symptoms in patients 
with dementia-related psychosis in two clinical studies. In addition, pimavanserin has a 
selective pharmacology and distinct safety profile compared with other antipsychotics, 
including no detrimental effects on cognitive and motor symptoms and lack of off-target 
toxicities. This safety profile offers the potentially unique and significant advantages over 
currently used antipsychotics in patients with neuropsychiatric symptoms associated with 
neurodegenerative disease. 
This placebo-controlled study is a US FDA post-approval commitment that will substantially 
expand the safety database in adult and frail, elderly patients. It will enroll patients with 
prominent neuropsychiatric symptoms (e.g., delusions, hallucination, depression/dysphoria, 
apathy/indifference, disinhibition, irritability/lability, sleep disorder) associated with 
Parkinson’s disease and other neurodegenerative diseases, for whom there are no approved 
antipsychotic therapies. Subjects who complete this study will be eligible to enroll in an 
open-label extension study to further evaluate the safety of pimavanserin. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of pimavanserin 
compared to placebo in adult and elderly subjects with neuropsychiatric symptoms related to 
neurodegenerative disease. 


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2.1.1 
Primary Measure 
The primary measure for this study is treatment-emergent adverse events (TEAEs). 
2.2 
Secondary Objective 
The secondary objective of this study is to assess the safety and tolerability of pimavanserin 
compared to placebo in adult and elderly subjects with neuropsychiatric symptoms related to 
neurodegenerative disease, with respect to extrapyramidal symptoms and cognition. 
2.2.1 
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
• 
Change from Baseline to Week 8 in Extrapyramidal Symptom Rating 
Scale-Abbreviated (ESRS-A) 
• 
Change from Baseline to Week 8 in Mini-Mental State Examination (MMSE) 
2.3 
Exploratory Objective 
The exploratory objectives of this study are: 
• 
To assess the safety and tolerability of pimavanserin compared to placebo in adult and 
elderly subjects with neuropsychiatric symptoms related to neurodegenerative disease, 
as described by suicidality 
• 
To evaluate the benefit of pimavanserin compared with placebo in adult and elderly 
subjects with neuropsychiatric symptoms related to neurodegenerative disease 
2.3.1 
Exploratory Endpoints 
The exploratory endpoint for this study to assess the safety and tolerability of pimavanserin 
is: 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) score or Global Clinician 
Assessment of Suicidality (GCAS) scale (if the subject is not able to complete the 
C-SSRS in the Investigator’s judgment) 
The exploratory endpoints for this study to assess the benefit of pimavanserin are: 
• 
Change from Baseline to Week 8 in Clinical Global Impression-Severity (CGI-S) 
score for neuropsychiatric symptoms 
• 
Clinical Global Impression-Improvement (CGI-I) score at Week 8 for 
neuropsychiatric symptoms 
• 
Change from Baseline to Week 8 in 5-level EuroQol-5D (EQ-5D-5L) score 
• 
Change from Baseline to Week 8 in sleep disturbances (assessed by Sleep Disorder 
Inventory [SDI]) 


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3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in adult and elderly subjects with neuropsychiatric symptoms related to 
neurodegenerative disease. The duration of participation for individual study subjects will be 
up to 16 weeks. The end of the clinical study will be when the last subject completes the last 
scheduled assessment. Approximately 100 global sites will participate in this study. 
The study will have 3 periods (Figure S–1): 
• 
Screening period (3-28 days) 
• 
Double-blind treatment period (8 weeks) 
• 
Safety follow-up period (30 [+4] days) 
If the study is terminated for any reason, subjects remaining in the study will return to 
standard of care. 
3.2 
Screening Period (3-28 Days) 
During the Screening period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued. 
Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should be discontinued only if it is deemed 
clinically appropriate to do so and in consultation with the treating physician. 
3.3 
Double-blind Period (8 Weeks) 
The Baseline visit (Visit 2) may occur as soon as screening procedures are completed and 
subject eligibility has been confirmed. At Visit 2, subjects will be randomized in a 1:1 ratio to 
pimavanserin 34 mg daily (QD) or matching placebo. It is recommended that the subject take 
the study drug at approximately the same time each day. Assessments will be conducted at 
Week 0 (Baseline), 1, 2, 4, 6, and 8/early termination (ET). 
3.4 
Safety Follow-up Period (30 Days) 
Eligible subjects who successfully complete the 8-week double-blind period will be eligible 
to enroll in an open-label extension study. For subjects who discontinue prematurely from the 
study or who do not enroll in the open-label extension study, a safety follow-up telephone 
call visit should be conducted 30 (+4) days after the last dose of study drug. 


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4 SUBJECT ELIGIBILTY AND WITHDRAWAL CRITERIA 
4.1 
Subject Selection and Withdrawal 
To be eligible for this study, subjects must meet all of the inclusion criteria and none of the 
exclusion criteria. 
4.2 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Is a male or female ≥60 years of age 
2. Can understand the nature of the trial and protocol requirements and provide written 
informed consent. 
If the subject is deemed not competent to provide informed consent, the following 
requirements for consent must be met: 
a. The subject’s legally acceptable representative (LAR) (or study 
partner/caregiver, if local regulations allow) must provide written informed 
consent 
b. The subject must provide written (if capable) informed assent 
3. Subject requires some or complete assistance with one or more of the following: 
a. Instrumental activities of daily living (communication, transportation, meal 
preparation, shopping, housework, managing medications, managing personal 
finances) OR 
b. Basic activities of daily living (personal hygiene, dressing, eating, maintaining 
continence or transferring) 
4. Meets clinical criteria for at least one of the following disorders, with or without 
cerebrovascular disease (CVD): 
a. Parkinson’s disease with or without dementia as defined by the Movement 
Disorder Society’s Task Force (Appendix B) 
b. Dementia with Lewy bodies (DLB) (Appendix C) 
c. All-cause dementia, possible or probable Alzheimer’s disease (AD) 
(Appendix A) 
d. Frontotemporal degeneration spectrum disorders, including possible or 
probable: 
i. Behavioral variant frontotemporal dementia (Appendix D) 
ii. Progressive supranuclear palsy (Appendix E) 
iii. Corticobasal degeneration (Appendix F) 


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e. Vascular dementia, including post-stroke dementia, multi-infarct dementia 
and/or subcortical ischemic vascular dementia (SIVD) (Appendix G) 
5. Has an MMSE score ≥6 at Visit 1 (Screening) and Visit 2 (Baseline) 
6. Has neuropsychiatric symptoms severe enough to warrant treatment with an 
antipsychotic agent, as evidenced by the Neuropsychiatric Inventory (NPI) score 
(Frequency×Severity) ≥4 on at least one of the following domains at Visit 1 
(Screening) and Visit 2 (Baseline) (the domains at Screening and Baseline can be 
different): 
a. Domain A Delusions; OR 
b. Domain B Hallucinations; OR 
c. Domain D Depression/Dysphoria; OR 
d. Domain G Apathy/Indifference; OR 
e. Domain H Disinhibition; OR 
f. Domain I Irritability/Lability; OR 
g. Domain K Sleep  
7. Has a CGI-S score of ≥4 when assessing neuropsychiatric symptoms at Visit 1 
(Screening) and Visit 2 (Baseline) 
8. Has lived at the current place of residence for at least 3 weeks prior to Visit 1 
(Screening) and there are no plans to move to a different location. 
9. Has a designated study partner/caregiver who meets the following requirements: 
a. In the Investigator’s opinion, is in contact with the subject frequently enough 
to accurately report on the subject’s symptoms and whether or not the subject 
is taking the study drug 
b. In the Investigator’s opinion, is considered reliable in providing support to the 
subject to help ensure compliance with study treatment, study visits, and 
protocol procedures 
c. Is fluent in the local language in which study assessments will be administered 
d. Agrees to participate in study assessments, has the capacity to provide 
informed consent, and provides written consent to participate in the study 
10. Can come to the clinic for study visits with a study partner/caregiver 
11. Has had a magnetic resonance imaging (MRI) or computed tomography (CT) scan of 
the brain within the last 3 years, and the scan or its final interpretation is available for 
review. If not available, a screening CT or MRI must be done during the screening 
period. 
12. If the subject is taking a cholinesterase inhibitor, memantine, or both: 


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a. the dose of the medication(s) must be stable for at least 12 weeks prior to 
Visit 2 (Baseline) and there must be no current plan to change the dose; OR 
b. if the medication(s) was discontinued, the discontinuation must occur no fewer 
than 2 weeks prior to Visit 2 (Baseline). 
13. If the subject is taking an antipsychotic medication at the time of screening, the 
antipsychotic medication must be discontinued 2 weeks or 5 half-lives (whichever is 
longer) prior to Visit 2. 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). 
14. If the subject is female, she must not be pregnant or breastfeeding. She must also 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 
or be abstinent for at least 1 month prior to Visit 2 (Baseline), during the study, and 
1 month following completion of the study. 
Abstinence as a method of contraception is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. This 
option is usually made for a specific moral, religious, legal, or health reason. If 
heterosexual intercourse does occur, an acceptable method of birth control is required. 
Acceptable methods of birth control include the following: 
• Condom, diaphragm, or cervical cap with spermicide 
• Hormonal contraception, including oral, injectable, transdermal, or implantable 
methods 
• Intrauterine device (IUD) 
4.3 
Exclusion Criteria 
A subject must not meet any of the following exclusion criteria to be eligible for the study: 
1. Is in hospice, is receiving end-of-life palliative care, or is bedridden 
2. Has neuropsychiatric symptoms that are primarily attributable to current delirium or 
substance abuse (i.e., neuropsychiatric symptoms not related to neurodegenerative 
disease) 
3. Has current evidence of an unstable neurological, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including 
cancer or malignancies that, in the judgment of the Investigator, would jeopardize the 
safe participation of the subject in the study or significantly interfere with the conduct 
or interpretation of the study 
4. Has a history of epilepsy 


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5. Has atrial fibrillation unless adequately anticoagulated 
6. Has a history of myocardial infarction, unstable angina, acute coronary syndrome, or 
cerebrovascular accident within the last 6 months prior to Visit 1 (Screening) 
7. Has any of the following: 
a. greater than New York Heart Association (NYHA) Class 2 congestive heart 
failure (Appendix J) 
b. Grade 2 or greater angina pectoris (by Canadian Cardiovascular Society 
Angina Grading Scale) (Appendix K) 
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsades de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
8. Has a history of human immunodeficiency virus (HIV) or hepatitis C infection 
9. Has a history of neuroleptic malignant syndrome or serotonin syndrome 
10. Has a known personal or family history of long QT syndrome or family history of 
sudden cardiac death 
11. Has any of the following ECG results at Visit 1 (Screening) or Visit 2 (Baseline): 
a. If the subject is not on citalopram, escitalopram, or venlafaxine: 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or venlafaxine: 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 
At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat set of triplicate 
ECGs may be performed during Screening at the discretion of the Medical Monitor.  
12. Has a heart rate <50 beats per minute. If bradycardia is secondary to iatrogenic or 
treatable causes and these causes are treated, a heart rate assessment can be repeated 
during the screening period. 
13. Has a clinically significant CNS abnormality that is most likely contributing to the 
dementia or findings on MRI or CT including: 
a. intracranial mass lesion (including but not limited to meningioma [>1 cm3 
with evidence of peritumoral edema] or glioma) 
b. vascular malformation 


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c. intracranial aneurysm >4 points by PHASES score (Appendix L) 
d. evidence of >4 hemosiderin deposits (definite microhemorrhage or superficial 
siderosis) 
14. Has clinically significant neuroimaging or laboratory abnormalities during Screening 
that in the judgment of the Investigator would jeopardize the safe participation of the 
subject in the study. In consultation with the Medical Monitor, these subjects may be 
rescreened after appropriate treatment of their medical condition. 
15. Has major surgery planned during the screening through end of the treatment or 
follow-up periods 
16. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
17. Has a body mass index (BMI) <18.5 kg/m2 or known unintentional clinically 
significant weight loss (i.e., ≥7%) over past 6 months 
18. The urine drug screen result at Visit 1 (Screening) indicates the presence of 
amphetamine/methamphetamine, barbiturates, cocaine, or phencyclidine (PCP). 
Subjects who test positive for amphetamines may be retested during Screening if they 
agree to abstain from the medication for the length of their participation in the study 
and if abstinence from medication usage is achieved at least 7 days prior to Visit 2 
(Baseline). The repeat Screening test must be negative for them to participate in the 
study. The presence of benzodiazepines, marijuana (THC), or opiates does not 
necessarily exclude the subject from the study.  
19. Is suicidal at Screening or Baseline as defined below: 
a. If the subject can complete the Columbia Suicide Severity Rating Scale 
(C-SSRS), he or she must not be actively suicidal at Visit 1 (Screening) or 
Visit 2 (Baseline) (including, an answer of “yes” to C-SSRS questions 4 or 5 
[current or over the last 6 months]) and must not have attempted suicide in the 
2 years prior to Visit 1 (Screening); OR 
b. If the subject is not able to reliably complete the C-SSRS in the Investigator’s 
judgment, the subject must not be suicidal as assessed by the Global Clinician 
Assessment of Suicidality (GCAS) score (i.e., a score of 3 or 4) based on 
Investigator’s assessment of behavior within the 3 months prior to Visit 1 
(Screening) or since-last-visit at Visit 2 (Baseline); OR 
c. The subject is actively suicidal in the Investigator’s judgment 


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20. Has participated in or is participating in a clinical trial of any investigational drug, 
device, or intervention, within 30 days or 5 half-lives, whichever is longer, of Visit 2 
(Baseline) 
21. Has previously been enrolled in any prior clinical study with pimavanserin or is 
currently taking pimavanserin. 
22. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
23. Is an employee or is a family member of an employee of Acadia Pharmaceuticals Inc. 
24. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
for any reason, including if the subject is judged to be a danger to self or others 
4.4 
Subject Withdrawal or Termination 
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 acceptable representative (LAR) because the subject is 
not competent to provide informed consent, the LAR has the right to withdraw the subject 
from the study at any time, and for any reason, without prejudice to the subject’s future 
medical care or any penalty or loss of benefits to the LAR. 
Subjects may be discontinued or withdrawn from the study for a number of reasons, 
including, but not limited to, those listed below: 
• 
Adverse event 
• 
Death 
• 
Lack of efficacy 
• 
Lost to follow-up 
• 
Non-compliance with study drug 
• 
Use of prohibited medication 
• 
Physician decision 
• 
Pregnancy 
• 
Protocol deviation 
• 
Study terminated by Sponsor 
• 
Subject or LAR withdraws consent 
• 
Other 
If at any time the C-SSRS or GCAS results for a given subject reveal potential suicidality, 
then the Investigator should assess the clinical significance of such results. If a clinically 


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significant risk of suicidality is identified for a subject, then the Investigator should 
discontinue the subject and implement appropriate treatment (Sections 6.3.5 and 6.3.6). 
Every reasonable effort should be made to complete Visit 7/ET and the safety follow-up 
period if a subject discontinues from the study for any reason. 
If a subject is lost to follow-up, every reasonable effort should be made to phone the subject 
approximately 4 weeks after last known contact with the subject in order to assess the 
subject’s current status. All phone contact with the subject should be documented. 
For subjects who continue to be followed for safety, SAEs should continue to be reported as 
described in Section 7.4.2. 
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 deems the AE to 
be chronic or stable. 
All SAEs will continue to be followed until such events have resolved or the Investigator 
deems them to be chronic or stable. 
Should a subject request or decide to withdraw, every reasonable effort will be made to 
complete and report observations as thoroughly as possible up to the date of withdrawal, 
including the evaluations specified at the ET visit outlined in Table S–1. Unless the subject 
has withdrawn consent to be contacted for this study, every reasonable effort 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). 
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, ethical, or business reasons affecting the continued performance of the study 
Regulatory authorities also have the right to terminate the conduct of the study in their region 
for any reason. 
4.5 
Prior and Concomitant Therapy 
4.5.1 
Prior Medications 
Prior medications are defined as any medication taken before the date of the first dose of 
study drug. 


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4.5.2 
Concomitant Medications 
Concomitant medications are defined as any medication taken on or after the date of the first 
dose of study drug. 
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). 
4.5.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Visit 7/ET as specified in Appendix H and Appendix I. These 
appendices do not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor or 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 designee. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor, or appropriate designee) as specified in Appendix H. 
If a subject is on a medication restricted by the protocol, the medication should be adjusted 
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) in 
consultation with the treating physician. 
The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. Subjects who require current treatment with a prohibited medication will be 
withdrawn from the study.  
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless: 
• 
the prohibited medication has been discontinued AND 
• 
withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the trial will be made by the 
Sponsor/Medical Monitor, with medical input from the Investigator, and will be documented. 
If a subject is allowed to remain in the trial, this will be reported as a major protocol 
deviation and not a waiver. 


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Permitted concomitant medications should remain at a stable dose throughout the study. 
Benzodiazepines (lorazepam up to 1 mg/day or equivalent) are allowed as rescue medication 
as needed for severe neuropsychiatric or behavioral disturbances (Appendix H). 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 34 mg (provided as 2×17 mg tablets) or 
matching placebo (2×placebo tablets). Placebo tablets will be size- and color-matched to the 
pimavanserin tablets. Tablets will be administered orally as a single dose once daily. 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 17 mg tablets and matching placebo tablets. 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin 17 mg tablets include the 
active compound (pimavanserin) and the following excipients: starch, microcrystalline 
cellulose, magnesium stearate, and the tablet coating is 
 
. The 
drug product is formulated with standard pharmaceutical excipients at 17 mg strength 
(20 mg of pimavanserin tartrate). 
Placebo tablets contain all of the same excipients as pimavanserin 17 mg tablets but do not 
contain any pimavanserin. 
Pimavanserin and placebo tablets are manufactured under current Good Manufacturing 
Practice. 
During the treatment period, study drug will be supplied in treatment kits with blister cards 
containing 20 tablets (10 days of treatment) each. Kits will be distributed in a quantity 
sufficient to ensure the subject has an adequate supply of study drug between study visits. 
5.1.2 
Product Storage and Stability 
Investigational product must be stored between 15°C to 30°C (59°F to 86°F) in a secure area 
with restricted access and according to local and national regulations. 
5.1.3 
Dosing and Administration 
The first dose of study drug will be administered at the site. Study drug kits will then be 
dispensed to the subject to take home. Each daily dose consists of two individual tablets that 
should be taken together. Subjects should be instructed to take two whole tablets, orally, once 
daily. Subjects should be instructed to not crush the tablets. The tablets may be taken with or 
without food. 


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5.1.4 
Method of Assigning Subjects to Treatment Groups 
At Week 0 (Visit 2), eligible subjects who meet inclusion and do not meet exclusion criteria 
will be randomized in a 1:1 ratio to receive either 34 mg pimavanserin or placebo. The 
randomization will be stratified by geographic region (North America, Europe, or rest of 
world). 
5.1.5 
Blinding 
Treatment assignments will be blinded to all study subjects, study partners/caregivers, 
Investigators, raters, site personnel, and Sponsor personnel who oversee the study. Details 
regarding medical emergency unblinding procedures are provided in Section 9.8. 
5.1.6 
Study Drug Compliance 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. 
If a subject shows significant undercompliance (<80% compliance) between any two 
scheduled visits, the Medical Monitor should be notified to determine if the subject remains 
eligible for the study. 
In the event that a subject is permanently unable to return study drug to the site (i.e., drug is 
lost, destroyed, or discarded), the subject/caregiver testimony is to be used in determining 
compliance. 
5.1.7 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported, irrespective of outcome, 
even if toxic effects were not observed (Section 7.4.4). All events of overdose are to be 
captured as protocol deviations. 
5.2 
Investigational Product Accountability Procedures 
The Investigator or designee will keep current and accurate records of the study drug 
dispensed, used, and returned for each subject to assure the regulatory authority and the 
Sponsor that the study drug is being handled appropriately. Subjects should be instructed to 
return all treatment kits, blister cards, and unused tablets to the Investigator at regularly 
scheduled clinic visits and any ET visits. Any study drug supplied is for use in this study only 
and should not be used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 


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At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction, as allowed by country specific regulations. 
Documentation of study drug destruction will be recorded and maintained by both the 
Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
Study specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table S–1. Every effort should be made to complete the required 
procedures and evaluations at the designated visits and times. 
6.1 
Screening Assessments 
6.1.1 
Neuropsychiatric Inventory 
The NPI was developed to assess psychopathology in dementia patients 
(Cummings et al. 1994). The original NPI evaluated 10 neuropsychiatric disturbances 
common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, 
irritability, euphoria, disinhibition, and aberrant motor behavior. Two other domains, 
nighttime behavior disturbances and appetite and eating abnormalities, were subsequently 
added to the NPI (Cummings 1997). At Screening, the degree of the patient’s 
neuropsychiatric symptoms will be evaluated using several of the domains of the NPI, as 
described in Section 4.2 Inclusion Criteria; patients with at least one individual domain score 
(frequency × severity) greater than or equal to 4 at Screening and Baseline (the domains at 
Screening and Baseline can be different) will be eligible for the study. 
6.1.2 
Mini-Mental State Examination 
The MMSE is a brief 30-point questionnaire that is used to quantitatively assess cognition 
(Folstein et al. 1975). The MMSE includes simple questions and problems in a number of 
areas: the time and place of testing, repeating lists of words, arithmetic, language use and 
comprehension, and copying a drawing. The MMSE is being used in this study to screen for 
cognitive impairment and as a safety measure. 
The MMSE will be assessed at all scheduled visits. 
6.1.3 
Medical History and Demographics 
A complete medical history will be obtained from each potential subject. Demographic 
information, including date of birth, gender, race, and ethnicity will be recorded as well. Any 
new medical condition beginning after the informed consent form (ICF) has been signed will 


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be captured as an AE. Subjects may be asked to provide pharmacy or medical records to 
substantiate the medication history. 
6.1.4 
Psychiatric History 
Details of the subject’s psychiatric history and treatment will be collected. 
6.1.5 
Dementia History 
Details of the subject’s dementia diagnosis and treatment will be collected, including the date 
that dementia was determined. 
6.1.6 
Neurological History 
Details of the subject’s neurological diagnosis and treatment will be collected, including the 
date that any neurological disease was determined. 
6.1.7 
Computed Tomography/Magnetic Resonance Imaging 
A CT or MRI head scan will be completed if the subject has not had brain imaging with a 
CT or MRI scan completed within the last 3 years (Section 4.2). The purpose of the scan is to 
evaluate criteria excluding a clinically significant CNS abnormality (Section 4.3). 
6.2 
Exploratory Efficacy Assessments 
6.2.1 
Clinical Global Impression – Severity and Improvement Scales 
The CGI–S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s neuropsychiatric symptoms at the time of assessment using the Investigator’s 
judgment and past experience with subjects who have the same disorder (Guy 1976). The 
CGI-S will be assessed at Screening and at all scheduled and unscheduled visits and will be 
used for exploratory efficacy analyses. 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s neuropsychiatric symptoms at the time of assessment, relative to the symptoms at 
Baseline. The CGI-I will be assessed at Weeks 1, 2, 4, 6, and 8/EOT and will be used for 
exploratory efficacy analyses. 
6.2.2 
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument used as a measure of health outcome 
(Kind 1996). It measures 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) each of which has 5 potential responses. The responses record 5 levels of 
severity (no problems/slight problems/moderate problems/severe problems/extreme 
problems) within a particular EQ-5D dimension. The EQ-5D-5L Proxy version 1 will be 
used. For this version, a caregiver (the proxy) is asked to rate the subject’s health-related 


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quality of life in their (the proxy’s) opinion. The EQ-5D-5L will be assessed at Weeks 0 and 
8/EOT and will be used for exploratory efficacy analyses. 
6.2.3 
Sleep Disorders Inventory 
The SDI is an expanded version of one item of the NPI (Tractenberg et al. 2003). It consists 
of the 7 subquestions from the NPI sleep disturbance item. Each of the subquestions was 
made into a separate question with frequency, severity, and caregiver distress rated by the 
caregiver with respect to the patient-participant for the 2 weeks prior to the visit. Thus, in 
contrast to a single rating for frequency and severity for all sleep disturbance-related 
behaviors, which would be incorporated into an overall NPI score, the SDI score is derived 
after the caregiver rates the frequency and severity of each of the 7 separate sleep disturbance 
symptoms. Caregiver distress ratings are not part of the SDI total score, but distress is 
measured. The SDI total score is calculated as the average of seven frequency 
ratings × average of seven severity ratings, with a range of 0-12. The SDI will be assessed at 
Weeks 0, 4, and 8/EOT and will be used for exploratory efficacy analyses. 
6.3 
Safety Assessments 
6.3.1 
Physical Examinations 
A physical examination will be conducted. 
6.3.2 
Vital Signs 
Vital signs will include resting respiration rate, sitting systolic and diastolic blood pressure, 
pulse rate, and temperature. The sitting blood pressure should be measured after the subject 
has been sitting for ≥3 minutes. 
6.3.3 
Height, Weight, and Body Mass Index 
Height will be reported in centimeters. 
Weight will be reported in kilograms. 
Body mass index will be calculated using the following formula: 
Weight (kg) / [height (m)]2. 
6.3.4 
Electrocardiograms 
All 12-lead electrocardiograms (ECGs) will be complete, standardized recordings. Triplicate 
ECGs will be completed at Visit 1 (Screening) and a single recording will be completed at all 
other times. All ECGs will be centrally read; the interpretation by the central cardiologist is 
considered the official interpretation. 


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At Visit 1 (Screening) the mean QTcF/QRS values of all the tracings of adequate quality will 
be used to determine eligibility. If a site performs additional ECGs beyond the set of triplicate 
ECGs prescribed at Screening or the single ECG prescribed at Baseline, the mean QTcF/QRS 
values of all the tracings of adequate quality will be used to determine eligibility. 
• At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat set of triplicate 
ECGs may be performed during Screening at the discretion of the Medical Monitor 
• At Baseline, a subject may be enrolled based on the machine read of the locally 
completed ECG. If the interpretation of the ECG by the central cardiologist indicates 
QTcF outside of the allowable range, the subject will be discontinued from the study, 
but this will not be considered a protocol deviation. 
The subject must rest in a supine position before the ECG is obtained. ECG tracings (paper or 
electronic) will be reviewed and interpreted by a qualified clinician. ECG tracings and results 
(heart rate, RR, PR, QRS, QT, QTcF, and QTcB interval duration) will be included and 
summarized in the subject's study records. 
6.3.5 
Columbia-Suicide Severity Rating Scale 
The C-SSRS monitors changes in suicidal thinking and behavior over time, in order to 
determine risk (Posner et al. 2011). The following four constructs are measured: the severity 
of ideation, the intensity of ideation, behavior, and lethality. 
The C-SSRS will be used to assess suicidal ideations and behaviors in subjects who are able 
to complete the assessment (subjects without dementia, defined as an MMSE ≥25, and 
subjects with dementia who the Investigator has determined can complete the C-SSRS). 
Whether or not the subject can complete the C-SSRS should be documented for each subject. 
For subjects who are able to complete the assessment, the Baseline/Screening version will be 
administered at Visit 1 (Screening), and the Since Last Visit version will be administered at 
subsequent visits. The C-SSRS results for each subject should be reviewed by the 
Investigator at each visit. If at any time the C-SSRS results for a given subject reveal 
potential suicidality, then the Investigator should assess the clinical significance of such 
results. If a clinically significant risk of suicidality is identified for a subject, then the 
Investigator should discontinue the subject and implement appropriate treatment 
(Section 4.4). 
6.3.6 
Global Clinician Assessment of Suicidality 
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 


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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 study 
partner/caregiver rating, and a clinician rating. 
If the subject is not able to reliably complete the C-SSRS in the Investigator’s judgment, the 
GCAS will be administered and used thereafter in the study. If the GCAS is administered, 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. 
As with the C-SSRS, if at any time the GCAS results for a given subject reveal potential 
suicidality, then the Investigator should assess the clinical significance of such results. If a 
clinically significant risk of suicidality is identified for a subject, then the Investigator should 
discontinue the subject and implement appropriate treatment (Section 4.4). 
6.3.7 
Extrapyramidal Symptom Rating Scale-Abbreviated 
The ESRS (Chouinard and Margolese 2005) was developed to assess drug induced 
movement disorders such as parkinsonism, akathisia, dystonia and tardive dyskinesia with 
established reliability, validity, and sensitivity. It consists of a questionnaire of parkinsonian 
symptoms, physician examination of parkinsonism, dyskinetic movements, and global 
impression of tardive dyskinesia. The ESRS-A, an accepted modified form of the original 
ESRS, will be used during the study to monitor for any worsening in extrapyramidal 
symptoms or signs at scheduled and unscheduled visits. 
6.3.8 
Laboratory Evaluations 
Clinical labs (including HbA1c at screening only) are encouraged, but not required to be 
completed under fasting conditions. The laboratory evaluations will include, but are not be 
limited to, the following: 
• 
Clinical chemistry serum tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
magnesium (Mg), carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine 
(CR), uric acid 
 Mg should only be performed at Visit 1 (Screening) 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Vitamin B12 
 Vitamin B12 should only be performed at Visit 1 (Screening) 


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o HbA1c 
 HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Thyroid stimulating hormone (TSH) and reflex free T4, if TSH is out of range 
 TSH/free T4 should only be performed at Visit 1 (Screening) 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, non-HDL cholesterol, very low density lipoprotein 
cholesterol 
• 
Pregnancy test 
o A serum pregnancy test should only be performed at Visit 1 (Table 6–1) for 
women of childbearing potential 
o A urine pregnancy test should be performed at all designated visits after Visit 1 
(Table 6-1) for women of childbearing potential 
 If urine cannot be obtained in women of childbearing potential, a 
serum pregnancy test should be done in its place 
• 
Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Absolute neutrophil count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
• 
Urinalysis 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, leukocyte 
esterase 
o Reasonable efforts should be made to collect a urine sample from all subjects. 
Where collection of a urine sample proves impractical or impossible (e.g., because 
the subject is incontinent), failure to collect a urine sample should be recorded in 
the subject’s CRF, and will not be considered a protocol deviation 


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• 
Urine toxicity screen 
o Subjects who test positive for amphetamines at Visit 1 (Screening) may be 
retested during Screening if they agree to abstain from the medication for the 
length of their participation in the study and if abstinence from medication usage 
is achieved at least 7 days prior to Visit 2 (Baseline). The repeat screening test 
must be negative for them to participate in the study. Any other amphetamine tests 
during the study must also be negative for them to continue participation in the 
study. 
o Subjects who test positive for benzodiazepines, THC, or opiates may continue in 
the study and last usage should be noted at the study visit. In addition, restrictions 
listed in Appendix H should be followed. 
o Reasonable efforts should be made to collect a urine sample at all scheduled visits 
as described in “Urinalysis” above 
Laboratory evaluations will be completed according to the schedule presented in Table 6–1 
and procedures detailed in the study Manual of Procedures. Additional safety testing may be 
performed at the discretion of the Investigator or designee. 
Table 6–1 
Safety Laboratory Evaluations 
Visit 
Testsa,b 
Visit 1 (Screening) 
CHEM, CBC, UA, urine toxicity screen, and serum pregnancy 
test 
Visit 2 (Week 0) 
CHEM, CBC, UA, and urine pregnancy test 
Visit 5 (Week 4) 
CHEM, CBC, UA, and urine toxicity screen 
Visit 7/ET  
(Week 8/EOT) 
CHEM, CBC, UA, urine toxicity screen, and urine pregnancy test 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; UA=urinalysis 
a    A pregnancy test is only required for women of childbearing potential. If urine cannot be obtained in 
women of childbearing potential, a serum pregnancy test should be done in its place. 
b    A vitamin B12 test, Mg level, HbA1c test, and TSH/free T4 test are only required at Visit 1 (Screening). 
6.4 
Safety Follow-up 
A 30-day safety follow-up telephone call visit should be completed for subjects who 
complete the study and decide not to continue into the open-label study or are not eligible for 


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the open-label study, as well as those who discontinue prematurely from the study. Subjects 
should have the following completed 30 (+4) days after last dose of study drug: 
• 
Assessment of concomitant medications/treatments 
• 
Assessment of AEs 
6.5 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following assessments 
generally should be recorded at each unscheduled visit: assessment of AEs, assessment of 
concomitant medications/treatments, measurement of vital signs, CGI-S, ESRS-A, and 
completion of the C-SSRS (Since Last Visit version) or the GCAS if the C-SSRS cannot be 
completed. The Investigator may perform any additional safety evaluations deemed by the 
Investigator to be clinically indicated. 
7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (US FDA 2012). 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug 
(e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
A 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 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) 


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• 
Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
Adverse events will be recorded from the time informed consent is obtained through the 
duration of the study. 
All AEs must be either resolved or stable at end of study. If ongoing at the end of the study 
the subject should be referred for appropriate treatment. 
For subjects who enroll into an open-label extension study, AEs will be recorded from the 
time informed consent is obtained in the present study until the first dose of study drug in the 
open-label study. 
For subjects who discontinue from the study or do not enroll into the open-label extension, 
AEs will be recorded from the time informed consent is obtained until 30 days after the last 
dose of study drug. 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
• 
Is fatal 
• 
Is immediately life threatening 
• 
Results in disability or permanent damage 
• 
Requires hospitalization 
• 
Prolongs existing hospitalization 
• 
Is a congenital anomaly or birth defect (in an offspring) 
• 
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 as a full admission to the hospital for diagnosis and treatment. 
This includes prolongation of an existing inpatient hospitalization. 


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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 
• 
Protocol procedures 
• 
Social hospitalization, defined as admission to the hospital as a result of inadequate 
family support or care at the subject’s primary residence  
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. 
7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
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 
7.2.2 
Relationship to Study 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 


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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 
• 
Concurrent illnesses 
7.2.2.1 
Duration 
The start and stop dates for AEs will 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 
7.2.2.2 
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 
7.2.2.3 
Action Taken with Study Drug 
• 
Dose not changed: No change in study drug 
• 
Drug interrupted: Study drug temporarily stopped 
• 
Drug withdrawn: Study drug discontinued permanently 
7.2.2.4 
Therapy 
• 
None: No new treatment instituted 
• 
Medication: New treatment initiated as a direct result of AE 
• 
Other: Other action required 
7.2.2.5 
Outcome 
• 
Recovered/resolved: Recovered or resolved 
• 
Recovered/resolved with sequelae: Recovered or resolved with sequelae 


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• 
Not recovered/not resolved: Not recovered or not resolved 
• 
Fatal: Death related to AE 
• 
Unknown: Unknown 
7.2.2.6 
Seriousness 
• 
Not serious 
• 
Serious 
7.2.3 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the information provided in the 
Reference Safety Information section of the current pimavanserin Investigator’s brochure. 
7.3 
Time Period and Frequency for Event Assessment and Follow-up 
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. 
7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
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 and the concomitant medication page.  
All AEs will be coded by Data Management using 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. 
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. 


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7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; 
use the appropriate form for initial and/or follow-up reporting. 
At a minimum, events identified by the Sponsor to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
IRB/EC, as per applicable regulations. These will be provided by the Sponsor after their 
assessment. For European Union member states, the Sponsor or its designee will provide 
reports of suspected unexpected serious adverse reactions (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 form (for initial and/or follow-up 
information) including available supporting documentation relevant to the event and fax or 
email (within 24 hours of discovery) to the contact information provided on the SAE form. 
Subjects will be followed until EOT/ET for any SAEs and/or other reportable information or 
until such events have resolved or the Investigator, in conjunction with the Sponsor, deems 
them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the study Follow-up Period should be reported if in the judgment 
of the Investigator there is “a reasonable possibility” that the event may have been caused by 
the product.   
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of 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 within 
24 hours of discovery to the Sponsor or its designee. Any female subject who becomes 
pregnant during the study will be followed through the first well-baby visit. 


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Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE forms. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or its 
designee on the Overdose form within 24 hours of discovery. 
8 CLINICAL MONITORING  
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 
9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan to be approved 
by the Sponsor prior to database lock. 
9.2 
Statistical Hypotheses 
No formal testing of efficacy or safety hypotheses is planned. Safety and efficacy outcomes 
will be summarized descriptively. 
9.3 
Sample Size Determination 
Approximately 1500 subjects will be screened to enroll approximately 750 subjects, allowing 
for a 50% screen failure rate. Approximately 375 subjects will be randomized to the 
pimavanserin group as well as the placebo group (i.e., 375 subjects in each treatment group). 
With an assumed dropout rate of 30% in the double-blind phase, 525 subjects in total are 
expected to complete the study. 
A sample size of 375 subjects in each treatment group ensures that within each treatment 
group, the probability of observing at least 1 AE with a true incidence of 1.0% is 0.977; 
the probability of observing at least 1 AE with a true incidence of 1.5% is 0.997; and the 
probability of observing at least 1 AE with a true incidence of 2.0% is 0.999. 


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9.4 
Subject Populations for Analysis 
The primary analyses will be based on the Safety Analysis Set. The Safety Analysis Set is 
defined as all subjects who take at least one dose of study drug. 
The Full Analysis Set (FAS) includes all randomized subjects who received at least one dose 
of study drug and have both a Baseline CGI-S and at least one post-Baseline value for the 
CGI-I or CGI-S. The FAS will be used for the analysis of all efficacy endpoints. 
9.5 
Description of Statistical Methods 
9.5.1 
Primary Analyses 
Safety results will be summarized by treatment group using descriptive statistics. Adverse 
events will be classified into standard terminology using MedDRA. 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 and no later than 
30 days after the last 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. 
9.5.2 
Secondary Analyses 
MMSE and ESRS-A observed values and change from Baseline will be summarized by 
treatment group and visit. The change from Baseline in the MMSE and ESRS-A scores will 
be summarized using mixed model repeated measures (MMRM). The model will include 
effects for region, treatment group, visit, treatment-by-visit interaction, Baseline score, and 
Baseline score-by-visit interaction. No formal comparisons between treatment groups are 
planned. The MMRM results for the pimavanserin and placebo groups will be tabulated by 
visit. 
9.5.3 
Exploratory Analyses 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. For the GCAS, the number and percentage of 
subjects with a score of 3 or 4 during the study will be tabulated. 
The CGI-I scores and the change from Baseline in the CGI-S and SDI scores will be 
summarized using MMRM. The model will include effects for region, treatment group, visit, 
treatment-by-visit interaction, Baseline score, and Baseline score-by-visit interaction. For 
CGI-I, the Baseline CGI-S score will be used as the Baseline covariate in the model. The 
change from Baseline in the EQ-5D-5L will be summarized using an ANCOVA model with 
effects for region, treatment group, and Baseline score. No formal comparisons between 


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treatment groups are planned. The MMRM results for the pimavanserin and placebo groups 
will be tabulated by visit. 
9.5.4 
Other Safety Analyses 
The serum clinical chemistry, hematology, and urinalysis results at each time point will be 
summarized by treatment group. Change from Baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically important (PCI) 
post-Baseline laboratory values will be summarized by treatment group at each post-Baseline 
visit and overall post-Baseline for selected parameters. The PCI criteria will be specified in 
the statistical analysis plan. 
Vital signs and body weight at Baseline and each post-Baseline visit will be summarized by 
treatment group. Change from Baseline values will also be summarized. 
The results of the physical examinations at each visit will be tabulated by treatment group. 
Electrocardiogram parameters at study visits 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. 
9.5.5 
Interim Analyses 
One or more unblinded interim analyses of data from subjects who have exited the study 
(i.e., completed, enrolled into the open-label extension, or terminated early) may be 
conducted in order to support safety and efficacy evaluations for regulatory submissions. 
9.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review interim safety data, 
including data on AEs and SAEs. The DSMB will be independent of the Sponsor and the 
Investigators and will be empowered to recommend stopping the study due to safety 
concerns. The DSMB may review blinded, unblinded or partially unblinded data, but the 
Sponsor and the Investigators will remain blinded to the data provided to the DSMB until the 
official unblinding of the database at the completion of the study. The membership, activities, 
responsibilities, and frequency of meetings will be described separately in the DSMB charter. 
9.7 
Measures to Minimize Bias 
Eligible subjects will be randomized into one of two treatment groups (pimavanserin or 
placebo) in a 1:1 ratio using an interactive response technology (IRT) system. The 
randomization will be stratified by geographic region (North America, Europe, or rest of 
world). The assignments will be based on a pre-generated permuted-block randomization 


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schedule. Blinding will be assured by restricting access of Investigators and Sponsor 
personnel and/or designee to the treatment codes, and providing identical tablets and 
packaging for the pimavanserin and placebo treatments. 
9.8 
Breaking the Study Blind/Subject Code 
For the final analysis, the treatment codes for all subjects will be released to the Sponsor after 
all subjects have completed the study and the clinical database is locked. 
For DSMB safety reviews, the treatment codes will be released to an independent 
statistician/programmer to produce unblinded statistical outputs. The Sponsor and the 
Investigators will remain blinded. 
One or more unblinded interim analyses of data from subjects who have exited the study 
(i.e., completed, enrolled into the open-label extension, or terminated early) may be 
conducted (Section 9.5.5), and unblinding of the Sponsor to individual treatment assignment 
as part of such analysis is permitted. 
Other than in the situations described above, unblinding of individual treatment assignment 
during the study is discouraged. The Investigator may break the blind in the event of a 
medical emergency if it is considered necessary for the care of the subject. The Investigator 
should attempt whenever possible to contact the Medical Monitor before unblinding a 
subject’s treatment to discuss the event. Lack of Medical Monitor contact does not preclude 
the Investigator from unblinding the subject. In an emergency situation, the subject’s 
treatment assignment may be obtained by the Investigator from the IRT system. Details of the 
process to be followed are provided in a separate IRT manual. In the event that the IRT 
system is used to perform a code break, the Sponsor or designee will be notified immediately 
via an automated notification from the IRT system that an unblinding has occurred. The 
notification only alerts the Sponsor or designee that the unblinding occurred, and does not 
include any information about the unblinded subject’s treatment assignment. 
10 STUDY MANAGEMENT AND DATA COLLECTION 
10.1 Data Collection and Management Responsibilities 
All documents required for the conduct of the study as specified in the ICH 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 authorities. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), regulatory authorities (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 


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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. 
10.2 Source Documents 
All study specific information obtained at each study visit must be recorded in the subject’s 
record (source documentation), and then entered into a validated electronic data capture 
(EDC) database by trained site personnel. The source documentation may consist of source 
notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 
10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs. The 
Investigator and his or 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 data, visit 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. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs or other documents submitted to the Sponsor or designees, subjects must be 
identified by a Subject Identification Number only. Documents that are not for submission to 
the Sponsor or designees (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. 
10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study 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 (US, 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 the Sponsor can 


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notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
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, he or she 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 (Section 6.4). 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 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 regulatory authorities, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. 
No approval is required for notifications. 
11 QUALITY MANAGEMENT 
11.1 Risk Management 
The Sponsor utilizes the ICH E6 (GCP) Revision 2 risk management approach that includes 
methods to assure and control the quality of the trial proportionate to the risks inherent in the 
trial and the importance of the information collected. The intent is that all aspects of this trial 
are operationally feasible and that any unnecessary complexity, procedures, and data 
collection are avoided. The Sponsor’s risk management approach includes the following 
activities with a focus on critical processes and critical study data: 
• Risk Identification: identification of risks to critical study processes, governing 
systems, investigational product, study design, data collection, and recording. 


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• Risk Evaluation: identified risks are evaluated by considering the following factors: 
(a) likelihood of error occurrence, (b) impact on human subject protection and data 
integrity, and (c) detectability of errors. 
• Risk Control: risks that can be reduced (e.g., mitigating) or can be accepted are 
differentiated. Risk mitigation activities are incorporated in protocol design and 
implementation, study plans, training, processes, and other documents governing the 
oversight and execution of study activities. Where possible, predefined quality 
tolerance limits are to be defined to identify systematic issues that can impact subject 
safety or data integrity and deviations from the predefined quality tolerance limits will 
trigger an evaluation and possibly an action. Contingency plans are developed for 
issues with a high risk factor that cannot be avoided. 
• Periodic Risk Review, communication and escalation of Risk Management activities 
during trial execution and risk outcome reporting in the Clinical Study Report (CSR). 
11.2 Quality Control and Quality Assurance 
The Sponsor or designees 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 Sponsor’s or designee’s monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH Guidance on GCP and the Sponsor’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. 
The Sponsor’s or designee’s 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. 


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12 ETHICAL CONSIDERATIONS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH GCP, and other applicable regulatory requirements. 
The study will be performed in accordance with the US Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 
54, 56, and 312), and ICH Guidance on GCP (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 will be signed by an Investigator and/or Coordinating Investigator who 
will be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator 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 Investigator 
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 Investigator 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. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject or subject’s 
LAR prior to any screening procedures. The subject’s caregiver must also provide written 
agreement prior to any screening procedures. 
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. 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 or designee 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. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 


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The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject. Any revision must be submitted to the appropriate IRB/EC for 
review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject or subject’s LAR must be given a copy of the signed informed consent and the 
original maintained in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
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’s caregiver must also indicate their understanding of the study and their role as a 
caregiver to the subject during the study. The subject’s caregiver must provide written 
agreement prior to any screening visit procedures being performed indicating their agreement 
to participate in the study in the caregiver role. 
13 PUBLICATION PLAN 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 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.


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SAP_001.pdf: 
Official Title: A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-
controlled, Safety Study of Pimavanserin Therapy in Adult and Elderly Subjects 
Experiencing Neuropsychiatric Symptoms Related to Neurodegenerative Disease 
NCT Number: NCT03575052 
Document Date: 23 May 2022 
 


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STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-046 
Protocol Title: 
A Phase 3b, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Safety Study of Pimavanserin 
Therapy in Adult and Elderly Subjects With 
Neuropsychiatric Symptoms Related to 
Neurodegenerative Disease 
Drug: 
Pimavanserin 
Sponsor:  
Acadia Pharmaceuticals Inc. 
 
 
Version No. and Date 
Version 4.0, 23 May 2022 
 
 
 
 
 
 
 
 
 
 


Protocol ACP-103-046 
Version 4.0 
Statistical Analysis Plan 
23 May 2022 
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SIGNATURE/APPROVAL PAGE 
AUTHOR 
 
 
_________________________________________________________________________ 
 
Date 
Director, Biostatistics 
Acadia Pharmaceuticals Inc. 
 
 
APPROVERS 
 
 
 
_________________________________________________________________________ 
 
Date 
Director, Clinical Research 
Acadia Pharmaceuticals Inc. 
 
 
 
_________________________________________________________________________ 
 
Date 
Executive Director of Biostatistics, Biometrics 
Acadia Pharmaceuticals Inc. 
 
 
 
 
 
 
 
See appended electronic signature page 
See appended electronic signature page 


Signature Page for ACP-103-046 Statistical Analysis Plan v4
Signature Page for ACP-103-046 Statistical Analysis Plan v4
Approve
s
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Protocol ACP-103-046 
Version 4.0 
Statistical Analysis Plan 
23 May 2022 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF TABLES ..................................................................................................................... 8 
LIST OF FIGURES ................................................................................................................... 8 
ABBREVIATIONS .................................................................................................................... 9 
1 
INTRODUCTION ....................................................................................................... 11 
2 
OBJECTIVES .............................................................................................................. 11 
2.1 
Primary Objective ..................................................................................................... 11 
2.1.1 
Primary Measure ....................................................................................................... 11 
2.2 
Secondary Objectives ............................................................................................... 11 
2.2.1 
Secondary Safety Endpoints ..................................................................................... 11 
2.3 
Exploratory Objectives ............................................................................................. 12 
2.3.1 
Exploratory Endpoints .............................................................................................. 12 
3 
STUDY DESIGN ......................................................................................................... 12 
3.1 
General Study Design ............................................................................................... 12 
3.2 
Schedule of Assessments .......................................................................................... 15 
3.3 
Randomization .......................................................................................................... 18 
3.4 
Blinding .................................................................................................................... 18 
3.5 
Determination of Sample Size .................................................................................. 18 
3.6 
Coronavirus Disease 2019 ........................................................................................ 18 
3.7 
Geopolitical Conflict in Ukraine............................................................................... 19 
4 
ANALYSIS SETS ........................................................................................................ 19 
4.1 
Randomized Analysis Set ......................................................................................... 19 
4.2 
Safety Analysis Set ................................................................................................... 19 
4.3 
Full Analysis Set ....................................................................................................... 19 
5 
DATA HANDLING CONVENTIONS ........................................................................ 19 
5.1 
General Data Reporting Conventions ....................................................................... 19 
5.2 
Derived Variables ...................................................................................................... 20 
5.2.1 
Neuropsychiatric Inventory ...................................................................................... 20 
5.2.2 
Clinical Global Impression Scale – Severity ............................................................ 21 
5.2.3 
Clinical Global Impression Scale – Improvement .................................................... 21 
5.2.4 
EQ-5D-5L Proxy Version 1....................................................................................... 21 


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5.2.5 
Sleep Disorders Inventory ........................................................................................ 22 
5.2.6 
Columbia-Suicide Severity Rating Scale .................................................................. 22 
5.2.7 
Global Clinician Assessment of Suicidality.............................................................. 23 
5.2.8 
Extrapyramidal Symptom Rating Scale-Abbreviated............................................... 24 
5.2.9 
Mini-Mental State Examination................................................................................ 24 
5.3 
Analysis Visit Windows ............................................................................................ 25 
5.3.1 
Unscheduled Assessments ........................................................................................ 25 
5.3.2 
Multiple Measurements within Visit Windows ........................................................ 25 
5.4 
Data Handling Conventions ...................................................................................... 26 
5.4.1 
Missing or Incomplete Date for Last Dose of Study Drug ....................................... 26 
5.4.2 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications ...... 26 
5.4.3 
Missing or Incomplete Dates for Adverse Events .................................................... 26 
5.4.4 
Missing Severity Assessment for Adverse Events .................................................... 26 
5.4.5 
Missing Relationship to Study Drug for Adverse Events ......................................... 26 
5.4.6 
Character Values of Clinical Laboratory Variables ................................................... 27 
6 
SUBJECT DISPOSITION ........................................................................................... 27 
7 
PROTOCOL DEVIATIONS ........................................................................................ 27 
8 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .................... 28 
8.1 
Demographics ........................................................................................................... 28 
8.2 
Disease Characteristics ............................................................................................. 28 
8.3 
Neuropsychiatric Inventory (NPI) ............................................................................ 29 
9 
MEDICAL HISTORY ................................................................................................. 29 
10 
PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION ................... 29 
10.1 
Prior Medication ....................................................................................................... 29 
10.2 
Concomitant Medication........................................................................................... 30 
10.3 
Post-Treatment Medication ....................................................................................... 30 
10.4 
COVID-19 Related Medications .............................................................................. 30 
11 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 30 
11.1 
Exposure to Study drug............................................................................................. 30 
11.2 
Measurement of Study Drug Compliance ................................................................ 30 
12 
EFFICACY ANALYSES ............................................................................................. 31 
12.1 
Exploratory Efficacy Endpoints ................................................................................ 31 
12.2 
Adjustment for Covariates ........................................................................................ 31 


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12.3 
Handling of Missing Data ......................................................................................... 31 
12.4 
Multiple Comparisons/Multiplicity .......................................................................... 31 
12.5 
Examination of Subgroups........................................................................................ 31 
13 
METHODS OF EFFICACY ANALYSES .................................................................. 32 
13.1 
Analysis of Efficacy Endpoints ................................................................................ 32 
13.2 
Mixed Model Repeated Measures (MMRM) ........................................................... 32 
13.3 
Analysis of Covariance (ANCOVA) ......................................................................... 33 
13.4 
Exploratory Efficacy Analyses ................................................................................. 33 
13.4.1 
CGI-S ........................................................................................................................ 33 
13.4.2 
CGI-I ......................................................................................................................... 34 
13.4.3 
SDI ............................................................................................................................ 34 
13.4.4 
EQ-5D-5L ................................................................................................................. 34 
14 
SAFETY ANALYSES ................................................................................................. 35 
14.1 
Adverse Events ......................................................................................................... 35 
14.1.1 
Primary Safety Analyses ........................................................................................... 36 
14.1.2 
Assessment of the Impact of COVID-19 on Adverse Events ................................... 37 
14.2 
Secondary Safety Analyses ....................................................................................... 37 
14.2.1 
ESRS-A ..................................................................................................................... 37 
14.2.2 
MMSE ....................................................................................................................... 37 
14.3 
Other Safety Analyses ............................................................................................... 38 
14.3.1 
Clinical Laboratory Variables ................................................................................... 38 
14.3.2 
Chemistry .................................................................................................................. 38 
14.3.3 
Hematology ............................................................................................................... 39 
14.3.4 
Urinalysis .................................................................................................................. 39 
14.3.5 
Methods of Analysis for Clinical Laboratory Variables ........................................... 39 
14.3.6 
Vital Signs ................................................................................................................. 42 
14.3.7 
Electrocardiogram (ECG) ......................................................................................... 43 
14.3.8 
Physical Examination ............................................................................................... 45 
14.3.9 
Suicidality ................................................................................................................. 45 
15 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES .. 46 
16 
UNBLINDED INTERIM ANALYSES ....................................................................... 46 
16.1 
General Procedure..................................................................................................... 46 
16.2 
Interim Analysis 1 ..................................................................................................... 46 
17 
DATA MONITORING/REVIEW COMMITTEE ....................................................... 47 


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Statistical Analysis Plan 
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18 
COMPUTER METHODS ........................................................................................... 47 
19 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ....................................... 47 
20 
REFERENCES ............................................................................................................ 48 
21 
APPENDICES ............................................................................................................. 49 
21.1 
Summary of Version Changes ................................................................................... 49 
 


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LIST OF TABLES 
Table 1 
Schedule of Events and Assessments for ACP-103-046 .................................. 16 
Table 2 
Analysis Visit Windows ................................................................................... 25 
Table 3 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ............................................................................. 41 
Table 4 
Criteria for Potentially Clinically Important Laboratory Values - 
Urinalysis ......................................................................................................... 42 
Table 5 
Criteria for Potentially Clinically Important Vital Signs ................................. 43 
Table 6 
Criteria for Potentially Clinically Important ECG Values ............................... 44 
 
LIST OF FIGURES 
Figure 1 Schematic of Study Design ....................................................................................... 14 
 


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ABBREVIATIONS 
AD 
Alzheimer’s disease 
ADP 
Alzheimer’s disease psychosis 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CI 
confidence interval  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
COVID-19 
coronavirus disease 2019 
DMP 
Data Management Plan 
DRP 
dementia related psychosis 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOS 
End-of-Study 
EQ-5D-5L 
5-level EuroQol-5D 
ESRS-A 
Extrapyramidal Symptom Rating Scale-Abbreviated 
ET 
Early Termination 
GCAS 
Global Clinical Assessment of Suicidality 
IA 
interim analysis 
ISG 
Independent Statistical Group 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-model repeated measures 
msec 
Milliseconds 
PCHC 
Pareto Classification of Health Change 
PCI 
potentially clinically important 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDI 
Sleep Disorders Inventory 
SE 
standard error 


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SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
VAS 
visual analogue scale 


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Statistical Analysis Plan 
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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in the study protocol amendment 7 
dated 05 March 2021. Specifications for tables, figures, and listings are contained in a 
separate document. 
In order to support potential regulatory submissions, the analysis plan was modified from that 
as specified in the Protocol by including formal statistical comparisons between treatment 
groups for selected efficacy and safety endpoints, and defining various subgroups. In 
addition, a factor for Baseline anti-dementia medication use was added for CGI-S and CGI-I 
analysis models. 
For the Czech Republic, a country-specific protocol amendment (Amendment 7-CZ dated 
23 July 2019) specifies additional exclusion criteria for tachycardia and blood pressure 
readings, as well as other procedural details. 
For Bulgaria, a country-specific protocol amendment (Amendment 6-BG dated 23 July 2019) 
specifies that the designated study partner/caregiver must be in daily contact with the subject, 
as well as other procedural details. 
2 OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of pimavanserin 
compared to placebo in adult and elderly subjects with neuropsychiatric symptoms related to 
neurodegenerative disease. 
2.1.1 
Primary Measure 
The primary measure for this study is treatment-emergent adverse events (TEAEs). 
2.2 
Secondary Objectives 
The secondary objective of this study is to assess the safety and tolerability of pimavanserin 
compared to placebo in adult and elderly subjects with neuropsychiatric symptoms related to 
neurodegenerative disease, with respect to extrapyramidal symptoms and cognition. 
2.2.1 
Secondary Safety Endpoints 
The secondary endpoints for this study are as follows: 
• Change from Baseline to Week 8 in Extrapyramidal Symptom Rating Scale-
Abbreviated (ESRS-A) 
• Change from Baseline to Week 8 in Mini-Mental State Examination (MMSE) 


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2.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To assess the safety and tolerability of pimavanserin compared to placebo in adult and 
elderly subjects with neuropsychiatric symptoms related to neurodegenerative 
disease, as described by suicidality 
• To evaluate the benefit of pimavanserin compared with placebo in adult and elderly 
subjects with neuropsychiatric symptoms related to neurodegenerative disease 
2.3.1 
Exploratory Endpoints 
The exploratory safety endpoint for this study to assess the safety and tolerability of 
pimavanserin is: 
• Columbia-Suicide Severity Rating Scale (C-SSRS) or Global Clinician Assessment of 
Suicidality (GCAS) scale (if the subject is  not able to complete the C-SSRS in the 
Investigator’s judgement) 
The exploratory efficacy endpoints for this study to assess the benefit of pimavanserin are: 
• Change from Baseline to Week 8 in Clinical Global Impression-Severity (CGI-S) 
score for neuropsychiatric symptoms 
• Clinical Global Impression-Improvement (CGI-I) score at Week 8 for 
neuropsychiatric symptoms 
• Change from Baseline to Week 8 in the 5-level EuroQol-5D (EQ-5D-5L) scores, 
including both the Visual Analogue Scale (VAS) and the 5 level descriptive system  
• Change from Baseline to Week 8 in sleep disturbances (assessed by the Sleep 
Disorder Inventory [SDI]) 
3 STUDY DESIGN 
3.1 
General Study Design 
This study will be conducted as a Phase 3b, 8-week, randomized, double-blind, 
placebo-controlled, parallel group study in adult and elderly subjects with neuropsychiatric 
symptoms related to neurodegenerative disease.  
Subjects will receive once daily (QD) doses of pimavanserin 34 mg (provided as 2 x 17 mg 
tablets) or matching placebo. During the Treatment Period, clinic visits will be conducted at 
Baseline and Weeks 1, 2, 4, 6, and 8, or upon early termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the Baseline visit and at each 
subsequent visit starting with Week 2.  The subject and their study partner/caregiver will be 


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provided instructions for subject’s first dose of study drug on the day after the Baseline visit.  
It is recommended that the subject take the study drug at approximately the same time each 
day as a single, oral dose. 
A follow-up safety assessment will be conducted by telephone call at approximately 30 days 
after the last dose of study drug. 
Figure 1 illustrates the study design. 


Protocol ACP-103-046 
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Figure 1 Schematic of Study Design 
 
Abbreviation: R=randomization 
Note: Subjects who enroll in an open-label extension will not complete the Follow-up Safety Period. 
 
 
 


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3.2 
Schedule of Assessments 
The schedule of events and assessments for the study is presented in Table 1. 


Protocol ACP-103-046 
 
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Table 1 
Schedule of Events and Assessments for ACP-103-046 
 
Period 
 
Screening 
 
Baseline 
 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Day/Week 
Day -28 to -
3 
Week 0 
Week 1 
Week 2 
Week 4 
Week 6 
Week 8 
Unscheduled 
Visit 
Week 12 
Visit Number 
1 
2 
3 
4 
5 
6 
(EOT/ET) 
7 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
Psychiatric, dementia, and 
neurological history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
X 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
12-lead ECGb 
X 
X 
 
X 
 
 
X 
 
 
Clinical laboratory testsc 
X 
X 
 
 
X 
 
X 
 
 
Pregnancy testd 
X 
X 
 
 
 
 
X 
 
 
Urine drug screen 
X 
 
 
 
X 
 
X 
 
 
MMSE 
X 
X 
X 
X 
X 
X 
X 
 
 
NPI  
X 
X 
 
 
 
 
 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
 
 
C-SSRSe or GCASe 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESRS-A 
 
X 
X 
X 
X 
X 
X 
X 
 


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Table 1 
Schedule of Events and Assessments for ACP-103-046 (Continued) 
 
Period 
 
Screening 
 
Baseline 
 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Day/Week 
Day -28 to -
3 
Week 0 
Week 1 
Week 2 
Week 4 
Week 6 
Week 8 
Unscheduled 
Visit 
Week 12 
Visit Number 
1 
2 
3 
4 
5 
6 
(EOT/ET) 
7 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
EQ-5D-5L 
 
X 
 
 
 
 
X 
 
 
SDI 
 
X 
 
 
X 
 
X 
 
 
CT/MRIf 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
 
X 
X 
X 
 
X 
 
Study drug accountability 
 
 
 
X 
X 
X 
X 
X 
 
Abbreviations: CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-Severity; CRF=case report form; C-SSRS=Columbia-Suicide Severity Rating 
Scale; CT=computed tomography; ECG=electrocardiogram; EOT=end of treatment; EQ-5D-5L=5-level EuroQol-5D; ESRS-A=Extrapyramidal Symptom Rating 
Scale-Abbreviated; ET=early termination; GCAS=Global Clinician Assessment of Suicidality; MMSE=Mini–Mental State Examination; MRI=magnetic resonance imaging; 
NPI=Neuropsychiatric Inventory; SDI=Sleep Disorders Inventory 
a 
This visit is a safety follow-up telephone call visit for subjects who discontinue prematurely from the study or who do not participate in the long-term extension study. This 
visit will occur 30 (+4) days after the last dose of study drug. 
b 
At Visit 1, ECG should be completed in triplicate. At all other visits, a single 12-lead ECG should be completed. These should occur before blood sampling or at least 
30 minutes after blood sampling. 
c 
To include hematology, serum chemistry, prolactin levels, and urinalysis. Urinalysis requirement is not applicable to subjects who are unable to provide urine sample (e.g., 
incontinent subjects). Where collection of a urine sample proves impractical or impossible, failure to collect a urine sample should be recorded in the subject’s CRF, and will 
not be considered a protocol deviation. 
d 
A pregnancy test is only required for women of childbearing potential. Serum pregnancy should only be performed at Visit 1; a urine pregnancy test should be performed at 
all subsequent visits. If urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be done in its place.  
e 
Suicidal assessment is required. For subjects who are able to complete the assessment, the Baseline/Screening version of the C-SSRS will be administered at Screening, and 
the Since Last Visit version of the C-SSRS will be administered at all subsequent visits. The C-SSRS is preferred. If the subject is not able to complete the C-SSRS in the 
Investigator’s judgment, the GCAS should be administered and used thereafter in the study. 
f 
A CT or MRI should only be completed if a CT or MRI scan has not been performed in the last 3 years prior to screening.


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3.3 
Randomization 
At Baseline (Visit 2/Week 0), eligible subjects who meet all inclusion criteria and do not 
meet any exclusion criteria will be randomized in a 1:1 ratio to receive either pimavanserin 
34 mg or matched placebo, using an interactive response technology system. Randomization 
will be stratified by geographic region (North America, Europe, or rest of world). 
The treatment assignments will be based on a pre-generated permuted-block randomization 
schedule. Blinding will be assured by restricting assess of Investigators and Sponsor 
personnel and/or designee to the treatment codes, and providing identical tablets and 
packaging for the pimavanserin and placebo treatments. 
3.4 
Blinding 
Treatment assignments will be blinded to all study subjects, study partners/caregivers, 
Investigators, raters, site personnel, and Sponsor personnel who oversee the study. See 
Section 16 regarding interim analysis (IA) unblinding in order to support safety and efficacy 
evaluations for regulatory submissions. Details regarding medical emergency unblinding 
procedures are provided in Section 9.8 of the ACP-103-046 protocol. 
3.5 
Determination of Sample Size 
Approximately 1500 subjects will be screened to enroll approximately 750 subjects, allowing 
for a 50% screen failure rate. Approximately 375 subjects will be randomized to the 
pimavanserin group as well as the placebo group (i.e., 375 subjects in each treatment group). 
With an assumed dropout rate of 30% in the double-blind phase, 525 subjects in total are 
expected to complete the study. In the event that the dropout rate is higher than anticipated, 
more subjects may be enrolled to ensure that at least 500 subjects complete the study. 
A sample size of 375 subjects in each treatment group ensures that within each treatment 
group, the probability of observing at least 1 AE with a true incidence of 1.0% is 0.977; the 
probability of observing at least 1 AE with a true incidence of 1.5% is 0.997; and the 
probability of observing at least 1 AE with a true incidence of 2.0% is 0.999. 
3.6 
Coronavirus Disease 2019  
In March, 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in 
implementation of urgent safety measures designed to ensure subject safety. Mechanisms to 
record information on the potential impact of the COVID-19 pandemic on data itself, as well 
as data collection and integrity, were implemented (as detailed in the Data Management Plan 
[DMP] Appendix B). Recruitment efforts into ACP-103-046, and roll-overs into the 
open-label extension study (ACP-103-047), were paused. The impact of COVID-19 on 
statistical analysis is discussed in each of the relevant sections of this SAP. 


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3.7 
Geopolitical Conflict in Ukraine 
Due to the ongoing geopolitical conflict in Ukraine, some sites in Ukraine may not be able to 
respond to all database queries, source data verification by clinical  monitors may not be 
possible at specific sites, and Investigators may not be able to sign-off on subject eCRFs prior 
to database lock. However, all data will be included in the final analyses as specified in this 
SAP.  
In order to assess the potential impact of any affected Ukraine data on the final analysis, all 
analyses will also be performed excluding all data for those subjects in Ukraine where the 
data has been impacted by any of the non-standard data scenarios noted above.  
The study team will document all subject data impacted by the geopolitical conflict in 
Ukraine in a comprehensive note-to-file that will be included in the Trial Master File at study 
closure. 
4 ANALYSIS SETS 
4.1 
Randomized Analysis Set 
The Randomized Analysis Set will include all subjects who were randomized. Subjects will 
be classified according to their randomized treatment assignment.  
4.2 
Safety Analysis Set 
The Safety Analysis Set will include all randomized subjects who took at least 1 dose of 
study drug. Subjects will be classified according to their actual treatment received.  
4.3 
Full Analysis Set 
The Full Analysis Set will include all subjects in the Randomized Analysis Set who received 
at least one dose of study drug and have both a Baseline CGI-S and at least one post-Baseline 
value for either the CGI-I or CGI-S. Subjects will be classified according to the randomized 
treatment assignment. 
5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean (SE), standard deviation (SD), minimum, 
maximum, and median. Unless specified otherwise, means, medians, and confidence 
intervals (CIs) will be presented to one more decimal place than the raw data, and the 


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standard deviations and standard errors will be presented to 2 more decimal places than the 
raw data. . 
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at 
the nominal significance level of 5% for main effects and all confidence intervals (CIs) will 
be 2-sided 95% CIs. P-values will generally be presented to 4 decimal places; values less 
than 0.0001 will be presented as <0.0001. 
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). Categories with zero counts will not have zero 
percentages displayed. Percentages will be presented to 1 decimal place.  
When converting number of days to months, it will be calculated as the number of days 
divided by 365.25 and then multiplied by 12. When converting number of days to years, it 
will be calculated as the number of days divided by 365.25. 
All safety endpoints will be summarized using the Safety Analysis Set. The Full Analysis Set 
will be used for summaries of all efficacy endpoints. 
Descriptive summaries of all safety and efficacy endpoints will be provided.  
5.2 
Derived Variables 
In general, all assessment scale total scores and subscores will be derived within the analysis 
datasets. In the event that total scores and/or subscores are also collected on the electronic 
case report form (eCRF), the derived values will be used for all analyses. Both the raw and 
derived total scores will be presented in data listings. 
5.2.1 
Neuropsychiatric Inventory 
The Neuropsychiatric Inventory (NPI) is assessed at Screening and Baseline. 
The NPI was developed to assess psychopathology in dementia patients. The original NPI 
evaluated 10 neuropsychiatric disturbances common in dementia: delusions (domain A), 
hallucinations (domain B), agitation/aggression (domain C), depression/dysphoria (domain 
D), anxiety (domain E), elation/euphoria (domain F), apathy/indifference (domain G), 
disinhibition (domain H), irritability/lability (domain I), and aberrant motor behavior (domain 
J). Two additional domains, sleep (domain K) and appetite and eating disorders (domain L), 
were subsequently added to the NPI. At Screening, the degree of the patient’s 
neuropsychiatric symptoms will be evaluated using several of the domains of the NPI 
(delusions, hallucinations, depression/dysphoria, apathy/indifference, disinhibition, 
irritability/lability, and sleep). Patients with at least one individual domain score (frequency × 


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severity) greater than or equal to 4 at Screening and Baseline (the domains at Screening and 
Baseline can be different) will be eligible for the study. 
Individual domain total scores are calculated as frequency × severity. Missing scores will not 
be imputed. Thus, if either the frequency or severity is missing for a given domain then the 
domain total score will be missing.  
Each domain has an associated caregiver distress question, rated on a 5 point scale from 0=no 
distress to 5=very severe or extreme. The caregiver distress items will not be summarized but 
will be displayed in data listings. 
5.2.2 
Clinical Global Impression Scale – Severity  
The CGI-S is assessed at Screening, Baseline, Weeks 1, 2, 4, 6, and Week 8/ET visits.  
The CGI-S is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject's neuropsychiatric symptoms at the time of assessment using Investigator’s judgment 
and past experience with subjects who have the same disorder. The 7-point scores are: 
1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 
6=severely ill; 7=among the most extremely ill. Higher scores denote more severe 
neuropsychiatric symptoms. 
Missing CGI-S scores will not be imputed. 
5.2.3 
Clinical Global Impression Scale – Improvement  
The CGI-I is assessed at Weeks 1, 2, 4, 6, and Week 8/ET visits.  
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s neuropsychiatric symptoms at the time of the assessment, relative to the symptoms 
at Baseline. The 7-point scores are: 1=very much improved; 2=much improved; 3=minimally 
improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. Higher 
scores denote more severe neuropsychiatric symptoms. 
Missing CGI-I scores will not be imputed. 
5.2.4 
EQ-5D-5L Proxy Version 1 
The EQ-5D-5L is assessed at Baseline and Week 8/ET. 
The EQ-5D-5L is a standardized instrument used as a measure of health outcome. The 
EQ-5D-5L Proxy version 1 will be used in this study. In this version, a caregiver (the proxy) 
is asked to rate the subject’s health-related quality of life in their (the proxy’s) opinion. It 
consists of 2 components: the descriptive system and the visual analogue scale (VAS). 
The EQ-5D-5L descriptive system consists of 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression) each of which has 5 potential responses. The 


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responses record 5 levels of severity within a particular EQ-5D-5L dimension: 1=no 
problems; 2=slight problems; 3=moderate problems; 4=severe problems; 5=extreme 
problems.  The responses for the 5 dimensions are combined into a single 5-digit code that 
describes the subject’s health state. 
The EQ-5D-5L VAS records the subject’s health on a vertical visual analogue scale, where 
the upper endpoint is labeled “The best health you can imagine” and is numbered 100, while 
the lower endpoint is labeled “The worst health you can imagine” and is numbered 0. The 
EQ-5D-5L VAS will be treated as a continuous endpoint. 
Missing values will not be imputed for either the descriptive system or EQ-5D-5L VAS. 
5.2.5 
Sleep Disorders Inventory  
The SDI is assessed at Baseline, Week 4, and Week 8/ET. 
The SDI is an expanded version of one item of the Neuropsychiatric Inventory (NPI). It 
consists of the 7 subquestions from the NPI sleep disturbance item. Each of the subquestions 
was made into a separate question with frequency, severity, and caregiver distress rated by 
the caregiver with respect to the patient-participant for the 2 weeks prior to the visit. Thus, in 
contrast to a single rating for frequency and severity for all sleep disturbance-related 
behaviors, which would be incorporated into an overall NPI score, the SDI score is derived 
after the caregiver rates the frequency and severity of each of the 7 separate sleep disturbance 
symptoms. Caregiver distress ratings are not part of the SDI total score, but distress is 
measured. The SDI total score is calculated as the average of seven frequency 
ratings × average of seven severity ratings; thus, the total score has a range of 0-12 (higher 
scores indicate more severe sleep disorder).  
If one frequency rating and/or one severity rating is missing then the total score will be 
imputed as the average of the non-missing frequency ratings × the average of the non-missing 
severity ratings. Otherwise, the total score will not be derived. 
5.2.6 
Columbia-Suicide Severity Rating Scale  
The C-SSRS will be used to assess suicidal ideations and behaviors in subjects who are able 
to complete the assessment (subjects without dementia, defined as an MMSE≥25, and 
subjects with dementia who the Investigator has determined can complete the C-SSRS). The 
C-SSRS is assessed (when applicable) at Screening, Baseline, Weeks 1, 2, 4, 6, and Week 
8/ET visits .  
The C-SSRS monitors changes in suicidal thinking and behavior over time, in order to 
determine risk. Four constructs are measured: the severity of ideation, the intensity of 
ideation, behavior, and lethality. 


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For subjects who are able to complete the assessment, the Baseline/Screening version will be 
administered at Screening, and the Since Last Visit version will be administered at 
subsequent visits. The C-SSRS results for each subject should be reviewed by the 
Investigator at each visit. If at any time the C-SSRS results for a given subject reveal 
potential suicidality, then the Investigator should assess the clinical significance of such 
results. If a clinically significant risk of suicidality is identified for a subject, then the 
Investigator should discontinue the subject and implement appropriate treatment. 
There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish 
to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods 
(not plan) without intent to act; active suicidal ideation with some intent to act, without 
specific plan; active suicidal ideation with specific plan and intent. If a subject answers “yes” 
to any of these 5 questions, this subject will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide. If 
a subject answers “yes” to any of these 5 questions, this subject will be counted as having 
suicidal behavior. 
Missing C-SSRS item scores will not be imputed. 
5.2.7 
Global Clinician Assessment of Suicidality  
If the subject is not able to reliably complete the C-SSRS in the Investigator’s judgment, the 
GCAS will be administered and used thereafter in the study. The GCAS is assessed (when 
applicable) at Screening, Baseline, Weeks 1, 2, 4, 6, and Week 8/ET visits.  
If the GCAS is administered 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. As with the C-SSRS, if at any time the GCAS results for a given subject reveal 
potential suicidality, then the Investigator should assess the clinical significance of such 
results. If a clinically significant risk of suicidality is identified for a subject, then the 
Investigator should discontinue the subject and implement appropriate treatment. 
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 study 
partner/caregiver rating, and a clinician rating. 
Missing scores will not be imputed. 


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5.2.8 
Extrapyramidal Symptom Rating Scale-Abbreviated  
The ESRS-A is assessed at Baseline, Weeks 1, 2, 4, 6, and Week 8/ET. 
The ESRS was developed to assess 4 types of drug-induced movement disorders 
(Parkinsonism, akathisia, dystonia, and tardive dyskinesia) with established reliability, 
validity, and sensitivity. The ESRS-A, an accepted modified form of the original ESRS, will 
be used during the study to monitor for any worsening in extrapyramidal symptoms or signs 
at scheduled and unscheduled visits. 
The ESRS-A consists of 4 subscales and 4 clinical global impression movement severity 
(CGI-S) scales of Parkinsonism, dyskinesia, dystonia, and akathisia. 
The Parkinsonism subscale consists of 10 items, the dyskinesia subscale consists of 6 items, the 
dystonia subscale consists of 6 items, and the akathisia subscale consists of 2 items. Each item 
is scored on a 6-point scale: 0=absent; 1=minimal; 2=mild; 3=moderate; 4=severe; 5=extreme. 
The ESRS-A total score is the sum of the 24 item scores with a possible range of 0 to 120. 
Higher scores denote more severe drug-induced movement disorders.  
Each CGI-S scale of Parkinsonism, dyskinesia, dystonia, and akathisia is a single-item 6-point 
scale: 0=absent; 1=minimal; 2=mild; 3=moderate; 4=severe; 5=extreme, with higher scores 
indicating more severe movement disorders.   
If 4 or fewer items are missing, then the total score for a given subject and timepoint will be 
imputed as the mean of the non-missing items multiplied by 24 and rounded to the nearest 
integer. If more than 4 items are missing, the total score will not be derived. Missing ESRS-A 
item scores and subscale total scores of the 4 subscales will not be imputed. Missing CGI-S 
scores will not be imputed. 
5.2.9 
Mini-Mental State Examination  
The MMSE is assessed at Screening, Baseline, Weeks 1, 2, 4, 6, and Week 8/ET visits.  
The MMSE is a 30-item questionnaire that includes simple questions and problems in the 
following areas: time and place of testing, repeating lists of words, arithmetic, language use 
and comprehension, and copying or drawing.  
Each of the 30 items has 2 possible values: 0=incorrect; 1=correct. The MMSE total score 
will be derived as the sum of the 30 item scores, thus the total score has a potential range of 
0 to 30. Lower scores indicate more severe cognitive impairment. 
If 6 or fewer items are missing, then the total score for a given subject and timepoint will be 
imputed as the mean of the non-missing items multiplied by 30 and rounded to the nearest 
integer. If more than 6 items are missing, the total score will not be derived. 


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5.3 
Analysis Visit Windows  
Baseline of the study is defined as the last non-missing result, included results from repeated 
and unscheduled measurements, before first dosing of study drug. 
Efficacy and safety assessments will be summarized by analysis visit as presented in Table 2 
below. 
Table 2 
Analysis Visit Windows 
Analysis Visit Name 
Target Study Day1 
Study Day Interval 
Baseline  
1 
≤1 
Week 1 
8 
2 to 11 
Week 2 
15 
12 to 21 
Week 4 
29 
22 to 35 
Week 6 
43 
36 to 49 
Week 8 
57 
50 to 63 
Follow-up 
85 
64 to maximum 
1 
If the assessment date ≥ first dose date, study day = assessment date - first dose date + 1, otherwise 
study day = assessment date – first dose  date. Study day 1 is the date of first dose of study drug. 
5.3.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including early termination visits, will be 
considered for planned timepoint summaries. All assessments will be presented in data 
listings. 
5.3.2 
Multiple Measurements within Visit Windows 
If more than one assessment falls within a given window then the assessment closest to the 
target study day will be selected for the by-visit summaries. If two assessments are 
equidistant from the target day then the chronologically last assessment will be used for 
summary. Exceptions may be made for incomplete assessments, in which case, more 
complete assessments may be given priority.  Details are provided in a separate programming 
conventions document. 
For safety summaries where the most extreme values should be selected, e.g. overall 
post-baseline minimum and overall post-baseline maximum,  all non-missing post-Baseline 
values should be considered, regardless of whether the value is selected for the by-visit 
summaries. All results will be presented in data listings. 


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5.4 
Data Handling Conventions 
5.4.1 
Missing or Incomplete Date for Last Dose of Study Drug 
In the Safety Analysis Set, if the last dose date of study drug is missing for a subject who 
completed or early terminated from the study, then the date of the end-of-study/early 
termination visit will be used in the calculation of treatment duration. For the incomplete last 
dose date of the study drug, the imputation algorithms will be detailed in the analysis dataset 
specification document. The missing or incomplete dates will be displayed in the data listings 
as reported on the eCRF rather than the imputed dates. 
For data summarizations before final database lock, if a subject is still ongoing, then this 
subject’s last dose date will be imputed using the database extract date.  
5.4.2 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 10 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as 
concomitant. The imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates will be displayed in the data listings as reported 
on the eCRF rather than the imputed dates. 
5.4.3 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When 
the chronological order of an AE onset relative to the study drug treatment period is unclear 
due to missing or incomplete date(s), the AE will be considered as treatment-emergent. The 
imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF 
rather than the imputed dates. 
5.4.4 
Missing Severity Assessment for Adverse Events 
If the severity is missing for a treatment-emergent AE, a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
and the actual values will be presented in data listings. 
5.4.5 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for a treatment-emergent AE, a causality of 
“Related” will be assigned. The imputed values for relationship to study drug will be used for 
incidence summaries, and the actual values will be presented in data listings. 


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5.4.6 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a summary due to, for 
example, a character string reported for a numeric variable, an appropriately determined 
coded value will be used in the summary. The coding algorithms will be detailed in the 
analysis dataset specification document. The actual values as reported in the database will be 
presented in data listings. 
6 SUBJECT DISPOSITION 
The number of sites that screened at least 1 subject, number of sites that randomized at least 
1 subject, number of subjects screened, and number of unique subjects screened will be 
summarized. In addition, the number of subjects enrolled at each site will also be tabulated.  
The number and percentage of subjects who completed the study or discontinued 
(all discontinued and by discontinuation reason) will also be summarized for the 
Randomized, Safety, and Full Analysis sets. A summary by region for the Safety Analysis set 
will also be presented. 
For subjects who were not included in the first interim analysis (IA-1) (see Section 16.2), 
early terminations of subjects due to COVID-19 related reasons will be captured in the 
eCRFs and summarized.   
For randomized subjects, the number and percentage of subjects in the analysis sets will be 
summarized. A listing will be provided displaying all subjects excluded from the analysis sets 
(if any), and will include reason(s) for exclusion.  
For subjects who participate in the screening phase and are screen failures, their 
demographics information (including age, sex, and primary race), screen failure reasons 
(the specific inclusion/exclusion criterion [or criteria] not met or other reason) and protocol 
version will be listed. If a subject is re-screened, then the re-screening subject ID and the 
final enrollment status (whether eventually enrolled) will also be displayed in this listing. In 
addition, the frequency that the screen failure reasons are reported will also be summarized. 
Note that a subject may be deemed ineligible for multiple inclusion/exclusion criteria and 
may be allowed to rescreen with the permission of the Medical Monitor, provided the screen 
failure was due to a temporary condition that subsequently resolved. 
For subjects who were not included in IA-1, screen failures due to COVID-19 will be 
captured in the eCRFs, and summarized. 
7 PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major 


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or minor will be detailed in the Protocol Deviation Management Plan. For subjects who were 
not included in IA-1, protocol deviations will also be assessed with respect to relationship to 
COVID-19.  
For randomized subjects, a summary of the number and percentage of subjects with major 
protocol deviations for each deviation category will be presented in three ways: all protocol 
deviations, COVID-19 related protocol deviations, and non COVID-19 related protocol 
deviations. 
Similarly, three data listings of major protocol deviations will be provided: All deviations, 
COVID-19 related protocol deviations, and non COVID-19 related protocol deviations. 
Additionally, a data listing of all minor COVID-19 related protocol deviations will be 
provided.  
In order to assess the potential impact of COVID-19 on missed visits, the proportion of 
missed visits will be tabulated by treatment arm for the Safety analysis set, computed as the 
number of total number missed visits divided by the total number of expected visits. This will 
be tabulated separately for IA-1 subjects, and subjects enrolled after IA-1, as a proxy for 
pre- and post-COVID-19 analyses. 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and Baseline characteristics will be summarized for the Randomized, Safety, 
and Full Analysis sets using descriptive statistics. Summaries by region using the Safety 
Analysis set will also be presented.  
8.1 
Demographics 
Demographic variables include age, sex, primary race (subjects of multi-racial background 
can only identify/select one primary race on eCRF, or choose “other” and specify), ethnicity, 
height, weight, body mass index (BMI), region, subject living situation, and partner/caregiver 
relationship. 
The reported age reflects a subject’s age at the informed consent date. Age and BMI will be 
presented as both continuous and categorical variables. Age categories will be presented as 
<65, 65 to 74, 75 to 84, and ≥85 years old. BMI categories (kg/m2) will be presented as <25, 
25 to 30, and >30. 
8.2 
Disease Characteristics 
Disease characteristics at Baseline will be summarized for the Randomized, Safety, and Full 
Analysis sets using descriptive statistics. MMSE total score, CGI-S, EQ-5D-5L VAS, SDI 
total score, and ESRS-A total score will be presented as continuous variables. CGI-S will be 
presented as a categorical variable using categories of 1 to 7, and MMSE total score will be 


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presented as a categorical variable using categories of ≤10, 11 to 17, 18 to 24, and 25 to 30. 
The number and percentage of subjects reporting suicidal ideation and suicidal behavior 
within the past 6 months and lifetime will be tabulated (for those subjects assessed with 
C-SSRS), and number and percentage of subjects reporting suicidality within the past 
3 months and lifetime will be tabulated (for those subjects assessed with the GCAS). 
Neuropsychiatric history will be summarized descriptively for continuous and categorical 
variables. Informed consent date will be used as the reference date when calculating duration 
of disease variables. 
For both the Disease Characteristics and Neuropsychiatric History, summaries by region will 
be presented using the Safety Analysis Set. 
8.3 
Neuropsychiatric Inventory (NPI) 
NPI will be summarized at Baseline for the Randomized, Safety and Full Analysis sets. Each 
of the individual domain total scores will be presented as continuous variables using 
descriptive statistics.  
9 MEDICAL HISTORY 
Medical and surgical history data will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.0 or newer. The subject incidence will be summarized for 
each system organ class (SOC) and preferred term for the Safety Analysis Set and Full 
Analysis Set. A subject will be counted only once per SOC or per preferred term for the 
summary. 
A listing of the SOC, preferred term, body system, verbatim term for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing at Screening will be provided. 
10 PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION 
Medications will be coded using WHO Drug Dictionary (WHODRUG-DDE-B2) 2018 
March or newer version. For concomitant medications, the number and percentage of 
subjects taking each drug class (ATC Level 3) and medication preferred term will be 
tabulated. A subject will be counted only once per drug class or per medication preferred term 
for the summary. Prior, concomitant, and post-treatment medications will be summarized 
separately using the Safety Analysis Set. 
10.1 Prior Medication 
Prior medication is defined as any medication with a start and stop date prior to the date of 
the first dose of study drug.  


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10.2 Concomitant Medication 
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of study drug and continuing after the first dose of study drug, or with a start date 
between the dates of the first and last doses of study drug, inclusive.  
10.3 Post-Treatment Medication 
Post-treatment medication is defined as any medication with a start date after the last dose of 
study drug.  
10.4 COVID-19 Related Medications 
For those subjects not included in IA-1, relationship to COVID-19 will be assessed by the 
investigator as detailed in the DMP Appendix B. Concomitant and post-treatment medication 
analyses described in Section 10.2 and Section 10.3 above will also be summarized by 
relationship to COVID-19 (Not related to COVID-19 vs. Related to COVID-19).  
11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety 
Analysis Set and Full Analysis Set. 
11.1 Exposure to Study drug  
Pimavanserin dose levels are expressed as free base. 
Duration of exposure is calculated as follows: 
Duration of exposure = last study drug dose date – first study drug dose date + 1 
For the categorical presentation of duration of exposure the number and percentage of 
subjects in each of the following categories will be displayed: <1 week (1 to 6 days), 1 to 
<2 weeks (7 to 13 days), 2 to <4 weeks (14 to 27 days), 4 to <6 weeks (28 to 41 days), 6 to 
<8 weeks (42 to 55 days) and ≥8 weeks (≥56 days). 
 Kaplan-Meier curves of duration of exposure will also be provided for each treatment group. 
11.2 Measurement of Study Drug Compliance 
Study drug compliance (in percentage) for a given subject is calculated as follows: 
Compliance = ൦ tablets dispensed − tablets returned
2 tablets
day
×  duration of exposure (days) 
൪× 100% 


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Study drug compliance will be summarized descriptively as both continuous and categorical 
variables. For the categorical presentation, the number and percentage of subjects in each of 
the following categories will be presented: <80%, 80 to 120%, and >120%. 
12 EFFICACY ANALYSES 
All efficacy analyses will be performed using the Full Analysis Set and the planned treatment 
assignments based on the randomization schedule. Descriptive summaries of all efficacy 
endpoints will be provided. 
12.1 Exploratory Efficacy Endpoints 
All of the efficacy endpoints are considered exploratory, and include the following: 
• Change from Baseline to Week 8 in CGI-S score for neuropsychiatric symptoms 
• CGI-I score at Week 8 for neuropsychiatric symptoms 
• Change from Baseline to Week 8 in SDI score 
• Change from Baseline to Week 8 in EQ-5D-5L scores (VAS and 5 level descriptive 
system) 
12.2 Adjustment for Covariates 
For continuous variables (except CGI-I) analyzed using a mixed model for repeated 
measured (MMRM) or an analysis of covariance (ANCOVA), the Baseline value of the 
endpoint being analyzed and region will be included as covariates as described in 
Sections 13.2 and 13.3. For CGI-I the Baseline CGI-S score and region will be included as 
covariates in the MMRM and ANCOVA analyses, and for CGI-I responder analyses region 
will be included as a stratification factor. 
12.3 Handling of Missing Data 
For selected endpoints missing values will be imputed with the previous observed value 
(including Baseline) for that subject, i.e. last observation carried forward (LOCF). 
12.4 Multiple Comparisons/Multiplicity 
No adjustments will be made for multiple comparisons for comparisons across multiple 
endpoints and across multiple subgroups. 
12.5 Examination of Subgroups 
Treatment comparisons will be made with respect to exploratory efficacy and secondary 
safety variables separately for each subgroup by: 
• Dementia related psychosis (DRP) (yes):  


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o Subjects with dementia from any cause, and having either a Baseline NPI 
delusions or hallucinations score (frequency × severity) ≥ 2 
• Primary cause of dementia due to Alzheimer’s disease  (AD) (yes): 
o Subjects with primary cause of dementia due to AD 
• Alzheimer’s disease psychosis (ADP) (yes) 
o Subjects with AD as the primary cause of dementia, and having either a 
Baseline NPI delusions or hallucinations score (frequency × severity) ≥ 2  
• Other-dementia psychosis (yes) 
o Subjects with vascular dementia, frontotemporal dementia-spectrum disorders, 
or dementia with Lewy bodies, and having either a Baseline NPI delusions or 
hallucinations score (frequency × severity) ≥ 2  
13 METHODS OF EFFICACY ANALYSES 
13.1 Analysis of Efficacy Endpoints 
Descriptive statistics for all exploratory efficacy endpoints listed in Section 12.1 will be 
tabulated by treatment group at scheduled timepoints. The summaries of the change from 
Baseline results will be presented by treatment group at scheduled timepoints. For change 
from Baseline values at each post-Baseline visit, LS means and standard errors (SE), the 
between-group difference in LS means with the corresponding 95% CI, p-value, and effect 
size will also be presented. 
13.2 Mixed Model Repeated Measures (MMRM) 
The MMRM method will be used for selected continuous exploratory endpoints, in which 
missing data is assumed to be missing at random. The dependent variable will be the change 
from Baseline. The independent variables in the model will include the fixed categorical 
effects of treatment group, region, visit, and treatment-by-visit interaction, as well as the 
continuous, fixed covariates of Baseline score and Baseline score-by-visit-interaction. An 
unstructured covariance matrix will be used to model the within patient errors, and the 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. 
Observed cases will be analyzed in the model and least squares (LS) means will be estimated 
using observed margins. 
In the event that the model fails to converge using the unstructured covariance matrix, then 
the following covariance structures will be modeled in the following order: 
1) Heterogeneous Toeplitz 


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2) Heterogeneous compound symmetry 
3) Heterogeneous autoregressive(1) 
4) Toeplitz 
5) Compound symmetry 
6) Autoregressive(1) 
7) Variance components  
The first covariance structure that allows for convergence will be selected for the final model. 
For change from Baseline values at each post-Baseline visit, LS means, standard errors (SEs), 
and the between-group difference in LS means with the corresponding two-sided 95% 
confidence intervals (CIs), p-values, and effect sizes will also be presented.  LS means ±SE 
over time for the change from Baseline values by treatment group will be presented in line 
plots. 
At each visit, the effect size (Cohen’s d) for the change from Baseline between the treatment 
groups will be calculated using the following formula: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠= 𝐿𝐿𝐿𝐿 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑒𝑒𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
√𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
 
The variance at a given visit will be obtained from the covariance matrix estimated for the 
MMRM model. The sign (+ or -) of the effect size will be chosen so that a positive value 
favors pimavanserin. 
13.3 Analysis of Covariance (ANCOVA) 
For those endpoints that are analyzed using ANCOVA (i.e., EQ-5D-5L VAS), the dependent 
variable will be the change from Baseline, and the independent variables in the model will 
include treatment group and region as factors, and Baseline score as a continuous covariate. 
LS means will be estimated using observed margins; the LSM, SE, LSM treatment 
difference, 95% CI of treatment difference, and p-value for treatment differences from the 
ANCOVA model will be reported. Observed cases excluding missing values, and the last 
observation carried forward (LOCF) method of imputation for missing data will be used. If 
necessary, the Baseline value will be carried forward. 
13.4 Exploratory Efficacy Analyses 
13.4.1 CGI-S 
Observed CGI-S scores will be summarized using descriptive statistics at Baseline, Weeks 1, 
2, 4, 6, and 8/ET. The change from Baseline values will be summarized descriptively at 
Weeks 1, 2, 4, 6, and Week 8/ET. The change from Baseline in CGI-S score will also be 


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analyzed using the MMRM model as described in Section 13.2, except that anti-dementia 
medication use at Baseline will be included in the model as a factor. 
13.4.2 CGI-I 
13.4.2.1 
MMRM 
Observed CGI-I scores will be summarized using descriptive statistics at Weeks 1, 2, 4, 6, 
and 8/ET. The CGI-I scores will also be analyzed using the MMRM model as described in 
Section 13.2, with the following modifications: 
• the dependent variable is the observed score 
• Baseline CGI-S score is used as the covariate 
• Anti-dementia medication use at Baseline will be included in the model as a factor 
13.4.2.2 
Responder Analysis 
A responder analysis will be conducted in which a CGI-I score of 1 (very much improved) or 
2 (much improved) will be counted as a responder. At each post-Baseline timepoint the 
proportion of responders will be summarized by treatment group.  
Two types of responder analyses will be performed: 
• Observed case responder analysis, in which subjects with missing values at a given 
visit are excluded from the analysis for that visit, will be performed 
• Missing values imputed as non-responders for the given visit 
The adjusted difference in percent responders between treatment groups (pimavanserin group 
minus placebo group) using the Cochran-Mantel-Haenszel weighting scheme stratified by 
region (North America, Europe, or rest of world), p-value, and Newcombe’s 95% CI will be 
presented.  
13.4.3 SDI 
Observed SDI scores will be summarized using descriptive statistics at Baseline, Week 4, and 
Week 8/ET. The change from Baseline values will be summarized descriptively at Week 4 
and Week 8/ET. The change from Baseline in SDI score will also be analyzed using the 
MMRM model as described in Section 13.2.  
13.4.4 EQ-5D-5L  
13.4.4.1 
VAS ANCOVA 
The change from Baseline in the EQ-5D-5L VAS score will be summarized using an 
ANCOVA model with effects for region, treatment group, and Baseline score. 


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Observed EQ-5D-5L VAS scores will be summarized using descriptive statistics at Baseline 
and Week 8/ET. The change from Baseline values will be summarized descriptively at 
Week 8/ET. The change from Baseline in EQ-5D-5L VAS score will also be analyzed using 
OC and ANCOVA LOCF as specified in Section 13.3. 
13.4.4.2 
Descriptive System Categorical Analysis 
For each EQ-5D-5L dimension the proportion of subjects reporting no, slight, moderate, 
severe, and extreme/unable to perform activity will be summarized descriptively at each 
timepoint using both OC and LOCF. 
Change from Baseline in EQ-5D-5L health state will be assessed with the Pareto 
classification of health change (PCHC) method. Using this methodology, at Week 8/ET, each 
EQ-5D health state will be classified into one of four categories, relative to the Baseline 
health state: 
• Improved = improved on at least one dimension and not worsened on any other 
dimension 
• Mixed = improved on at least one dimension and worsened on at least one other 
dimension 
• No change = no changes in any dimension 
• Worsened = deterioration on at least one dimension and no improvement on any other 
dimension 
The proportion of subjects in each PCHC category will be summarized descriptively at 
Week 8/ET using both OC and LOCF. 
14 SAFETY ANALYSES 
Safety variables include AEs, TEAEs, clinical laboratory variables, vital signs, body weight, 
BMI, physical examinations, electrocardiogram (ECG), C-SSRS, GCAS, MMSE, and 
ESRS-A variables. The safety summaries will be presented for the Safety Analysis Set using 
descriptive statistics. An MMRM model will be applied to the ESRS-A and MMSE total 
score endpoints. Safety variables will be summarized by treatment group.  
14.1 Adverse Events  
All Adverse events (AEs) will be coded using MedDRA version 20.0 or newer. 
An AE will be considered a TEAE if it started on or after the first dose of study drug and no 
later than the last study drug dose date + 30. AEs reported on Day 1 based on pre-dose 
findings will not be considered as TEAEs.   


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For subjects enrolling in the long-term open-label study ACP-103-047, any AE started before 
the first dose of open-label study drug in Study ACP-103-047 will be considered as TEAE in 
Study ACP-103-046 but not in study ACP-103-047.  Similarly, any AE reported after the first 
dose of open-label study drug  in ACP-103-047 will be reported in association with the 
ACP-103-047 study only. 
14.1.1 Primary Safety Analyses 
TEAEs are the primary measure for this study. For the following summaries, the event counts 
and the number and percentage of subjects reporting TEAEs will be tabulated by treatment 
group:  
• TEAEs by SOC and preferred term (PT) 
• Most frequently reported TEAEs by SOC and PT 
− 
PTs reported by ≥ 5% of subjects in either treatment group 
• TEAEs by PT 
• TEAEs by maximum severity, SOC, and PT 
− 
if more than 1 AE occurs with the same PT for the same subject, the subject 
will be counted only once for that PT using the most severe occurrence 
• TEAEs related to study drug by SOC and PT 
• Treatment-emergent serious adverse events (TESAEs) by SOC and PT 
• TEAEs leading to study drug discontinuation or study termination by SOC and PT 
• AEs with fatal outcome by SOC and PT 
• TEAEs with fatal outcome (that occurred within 30 days of last dose) by SOC and PT 
For tabulations that include SOC and PT the display will be sorted alphabetically by SOC and 
then by descending subject frequency for the PTs based on counts in the combined treatment 
groups within each SOC. SOCs will not be included in the TEAEs by PT tabulation. This 
display will be sorted by descending subject frequency based on counts in the combined 
treatment groups. 
An AE listing by subject will display all events, including those which are not treatment-
emergent, and will include the verbatim term in addition to the MedDRA SOC and PT. This 
listing will also include all relevant eCRF data associated with the event: e.g. date of onset, 
date resolved, date of the first and last dose of study drug, severity, frequency, outcome, 
relationship to study drug, action taken with study drug, and required therapy. When a date is 
presented, the study day associated with the date will also be displayed. Separate listings will 


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be presented for subjects with SAEs, subjects with AEs leading to study drug discontinuation 
or study termination and subjects who died (if any). In these listings, an indicator for TEAEs 
will also be included. 
14.1.2 Assessment of the Impact of COVID-19 on Adverse Events 
The relationship of selected AEs to COVID-19 will be assessed by investigator as detailed in 
the DMP Appendix B, for those subjects who were not unblinded as part of the first interim 
analysis.  Each of the primary safety analyses described in Section 14.1.1 will be additionally 
summarized by relationship to COVID-19 (Not related to COVID-19 vs. Related to 
COVID-19). 
Both the Not related to COVID-19 and the Related to COVID-19 AE tables will be 
summarized using 2 sets of subjects: all subjects in the Safety analysis set, and subjects in the 
Safety analysis set that were not included in IA-1, as a proxy for pre- and post-COVID-19 
analyses. 
14.2 Secondary Safety Analyses 
The secondary endpoints for this study are change from Baseline to Week 8 in ESRS-A, and 
change from Baseline to Week 8 in MMSE. 
14.2.1 ESRS-A 
The ESRS-A total score and the 4 individual global CGI-S scores will be summarized using 
descriptive statistics at Baseline and Weeks 1, 2, 4, 6, and 8/ET. The change from Baseline 
scores will also be summarized at Weeks 1, 2, 4, 6, and 8/ET. 
The ESRS-A total score change from Baseline will be summarized using MMRM as 
specified in Section 13.2. The model will include categorical fixed effects for region, 
treatment group, visit, treatment-by-visit interaction, as well as the continuous fixed 
covariates for Baseline score and Baseline score-by-visit interaction. The MMRM results for 
the pimavanserin and placebo groups will be tabulated by visit. 
The individual item scores will be listed but not summarized. 
14.2.2 MMSE 
The MMSE total score will be summarized using descriptive statistics at Baseline, Weeks 1, 
2, 4, 6, and 8/ET. The change from Baseline scores will also be summarized at Weeks 1, 2, 4, 
6, and 8/ET. 
The MMSE total score change from Baseline will be summarized using MMRM as specified 
in Section 13.2. The model will include categorical fixed effects for region, treatment group, 
visit, treatment-by-visit interaction, as well as the continuous fixed covariates for Baseline 


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score and Baseline score-by-visit interaction. The MMRM results for the pimavanserin and 
placebo groups will be tabulated by visit. 
The individual item scores will be listed but not summarized. 
14.3 Other Safety Analyses 
14.3.1 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Screening, Baseline, Week 4, and Week 8/ET visits. 
In general, laboratory test results are collected from a central laboratory  
Due to COVID-19 disruptions it is possible that some test results may be collected from a 
local laboratory. A separate eCRF will capture local laboratory results in order to facilitate 
medical monitoring of subject safety. Local laboratory results will not be included in any 
summary data analysis; they will, however, be included in data listings, as well as a separate 
local laboratory PCI listing.  All results (central and local) will be displayed in Système 
International [SI] units. 
14.3.2 Chemistry 
Clinical chemistry serum tests include the following: 
• Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
– Mg should only be performed at Screening  
• Alaninine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), 
lactate dehydrogenase (LDH) 
• Glucose 
• Albumin (ALB), total protein 
• Prolactin  
• Creatine kinase (CK)/creatine phosphokinase (CPK) 
• Lipid panel 
– total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, ratio, non-HDL-cholesterol, very low density 
lipoprotein cholesterol 


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• Magnesium (Mg), Vitamin B12, HbA1c, thyroid stimulating hormone (TSH) and 
reflex free T4 (if TSH is out of range) 
– these tests should only be performed at Screening 
• Serum pregnancy test 
– performed only at Screening for women of childbearing potential 
14.3.3 Hematology 
Hematology tests include the following: 
• Complete blood count (CBC) including: 
− 
White blood cell (WBC) count, absolute neutrophil count, complete 
differential (relative and absolute), hematocrit (Hct), hemoglobin (Hgb), red 
blood cells (RBC), platelets, reticulocyte count  
14.3.4 Urinalysis 
Urinalysis tests include the following: 
• Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
• A urine pregnancy test will be performed for all women of childbearing potential at 
Baseline and at each scheduled visit 
– If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done in its place 
14.3.5 Methods of Analysis for Clinical Laboratory Variables 
14.3.5.1 
Observed Values and Change from Baseline 
Clinical laboratory values reported as continuous values for hematology, chemistry and 
urinalysis will be summarized using descriptive statistics at Baseline and scheduled 
post-Baseline visits. The change from Baseline values will also be summarized at scheduled 
post-Baseline visits. 
The overall post-Baseline minimum and maximum observed and change from Baseline 
values will also be summarized. For urinalysis with categorical results, the number and 
percentage of subjects will be tabulated by category at Baseline and each scheduled 
post-Baseline visit. For the categorical urinalysis by-visit summary, the denominator is the 
number of subjects with non-missing values for the given parameter, visit, and treatment 
group. 
For hemoglobin, hematocrit and uric acid, by-visit as well as overall post-Baseline minimum 
and maximum will be presented for each gender as well as for both genders combined. 


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14.3.5.2 
Shift Tables 
Laboratory values will be summarized in shift tables to determine the number and percentage 
of subjects with values classified as below (low), within (normal), or above (high) normal 
ranges at each scheduled post-Baseline visit relative to the same classification at the Baseline 
visit. For the by-visit shift summary, the denominator is the number of subjects with 
non-missing values at Baseline and the given visit for the given parameter and treatment 
group.  
The shifts from Baseline to overall post-Baseline minimum and maximum will also be 
presented. The denominator is the number of subjects with non-missing Baseline and at least 
1 post-Baseline value for the given parameter and treatment group.  
For hemoglobin, hematocrit and uric acid, by-visit as well as overall post-Baseline minimum 
and maximum will be presented for each gender as well as for both genders combined. 
14.3.5.3 
Potentially Clinically Important (PCI) Laboratory Values 
The number and percentage of subjects with PCI laboratory values at scheduled post-
Baseline visits Week 4 and Week 8 and overall post-Baseline will be summarized by Baseline 
status (all or within normal range) for selected parameters. PCI criteria are listed in Table 3 
and 
.  Subjects with multiple PCI values for a given parameter will be counted only 
once for that parameter.  All post-Baseline values will be considered, including unscheduled 
and out of window values 
For the by-visit summary, the numerator for the percentage is the number of subjects with a 
post-Baseline PCI value for the given parameter, visit, and treatment group, and the 
denominator is the number of subjects with non-missing values for the given parameter, visit, 
and treatment group. For the overall post-Baseline summary, the numerator for the 
percentage is the number of subjects with at least 1 post-Baseline PCI value for the given 
parameter and treatment group, and the denominator is the number of subjects with at least 
1 post-Baseline value for the given parameter and treatment group. For hemoglobin, 
hematocrit and uric acid, the count and percentage of subjects with PCI values will be 
presented for each gender as well as for both genders combined. 


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Table 3 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole blood) 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin 
(female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55 
L/L 
<0.3 
>0.55 
Hematocrit (female) 
% 
<30 
>50 
L/L 
<0.3 
>0.5 
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper limit 
x 109/L 
≤1.5 
No upper limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum or plasma) 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase 
(CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
 


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Table 4 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis  
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥Moderate 
Protein 
Not Applicable 
≥100 mg/dL 
Glucose 
Not Applicable 
≥500 mg/dL 
 
14.3.5.4 
Data Listings 
All laboratory test results will be listed. The listings will include date and study day of 
collection. Out of range values will be flagged in the data listings (e.g., as ‘L’ or ‘H’). Central 
and local laboratory values will be presented separately. 
A listing of all PCI values will be provided. This listing will include all observations for those 
subjects and parameters for which at least one PCI value (including Baseline) was observed. 
Central and local laboratory PCI listings will be presented separately. 
The pregnancy results (positive or negative) for female subjects of childbearing potential will 
be presented in a listing. 
14.3.6 Vital Signs 
Vital signs are assessed at Screening, Baseline, Weeks 1, 2, 4, 6 and Week 8/ET visits. 
Due to COVID-19 disruptions it may be necessary for vital signs to be collected outside of 
the clinic by persons other than study site staff. These results will not be included in any 
summary data analysis; they will, however, be presented in data listings, and in a separate 
PCI listing of vitals measured by persons other than study site staff.  
14.3.6.1 
Vital Signs Variables 
Vital signs include height (only measured at Screening), weight, derived BMI, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), pulse rate, temperature, and respiratory rate. 
14.3.6.2 
Vital Signs Methods of Analysis 
Vital signs will be summarized using descriptive statistics at Baseline and all scheduled 
post-Baseline visits. The change from Baseline values will also be summarized at the 
scheduled post-Baseline visits. 
Vital sign values will be considered PCI if they meet the criteria listed in Table 4. The 
number and percentage of subjects with post-Baseline vital signs that are PCI will be 
summarized at scheduled post-Baseline visits and for overall post-Baseline. For the overall 
post-Baseline summaries, all post-Baseline values will be considered, including unscheduled 
and out of window values. Subjects with multiple PCI values for a given parameter will be 
counted only once for that parameter. For the by-visit summary, the numerator for the 


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percentage is the number of subjects with a post-Baseline PCI value for the given parameter, 
visit and treatment group, and the denominator is the number of subjects with non-missing 
values for the given parameter, visit and treatment group. For the overall post-Baseline 
summary, the numerator for the percentage is the number of subjects with at least 
1 post-Baseline PCI value for the given parameter and treatment group, and the denominator 
is the number of subjects with at least 1 post-Baseline value for the given parameter and 
treatment group.   
A listing of all PCI values will be provided (excluding those vitals collected by persons other 
than study site staff). There will be a separate PCI listing for vitals collected by persons other 
than study site staff. These listings will include all observations for those subjects and 
parameters for which at least one PCI value (including Baseline) was observed. 
Table 5 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed 
Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Weight 
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change 
from baseline. 
14.3.7 Electrocardiogram (ECG) 
In countries outside of the Czech Republic, ECG is performed at Screening, Baseline, Week 
2, and Week 8/ET. At the clinical sites in the Czech Republic, ECG is performed at all visits. 
For ECG data summaries, the common scheduled visits across all clinical sites will be used 
(i.e., Baseline, Week 2, and Week 8/ET). 
All tracings will be evaluated by a central reading laboratory, including any collected outside 
of the clinic due to COVID-19 disruptions when possible. At the Baseline visit the 
machine-read results will also be recorded. ECG data summaries, including the cardiologist’s 
interpretation, will be analyzed using the centrally evaluated data. All data, including the 
machine-read Baseline results, will be listed. 


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14.3.7.1 
ECG Variables 
ECG variables include heart rate, PR interval, RR interval, QRS interval, QT interval, and 
QTc intervals. QTc intervals include QTcB (Bazett’s formula) and QTcF (Fridericia’s 
formula). QTcF will also be categorized into the following categories (msec): 
• Observed: ≤450, 451 to 480, 481 to 500, and >500 
• Change from Baseline: ≤10, 11 to 30, 31 to 60, and >60 
14.3.7.2 
ECG Methods of Analysis 
14.3.7.2.1 
Observed Values and Change from Baseline 
Observed values and the changes from Baseline of ECG variables will be summarized using 
descriptive statistics at Baseline and all scheduled post-Baseline visits. For the QTcF 
categorical analysis, the number and percentage of subject in each category will be 
summarized at each scheduled visit as well as overall post-Baseline maximum. 
14.3.7.2.2 
PCI Values 
Electrocardiogram values will be considered PCI if they meet or exceed the criteria listed in 
Table 6. The number and percentage of subjects with PCI values will be summarized at each 
scheduled post-Baseline visits and for overall post-Baseline.  
For the by-visit summary, the numerator for the percentage is the number of subjects with a 
post-Baseline PCI value for the given parameter, visit and treatment group, and the 
denominator is the number of subjects with non-missing values for the given parameter, visit 
and treatment group. 
For the overall post-Baseline summary, the numerator for the percentage is the number of 
subjects with at least 1 post-Baseline PCI value for the given parameter and treatment group, 
and the denominator is the number of subjects with at least 1 post-Baseline value for the 
given parameter and treatment group; all post-Baseline values will be considered, including 
unscheduled and out-of-window values. 
A listing of all PCI values will be provided for those subjects and parameters for which at 
least 1 PCI value (including Baseline) was observed. 
Table 6 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
≥120 
PR Interval 
msec 
≥220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline 
msec 
>60 


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14.3.7.2.3 
Cardiologist Interpretations 
For cardiologist’s interpretations, the number and percentage of subjects with ECG results 
that are determined as normal or abnormal will be summarized at scheduled visits. The 
overall post-baseline worst interpretation will also be summarized (i.e. if a subject has one or 
more ECG results that are considered as abnormal, this subject will be counted in the 
abnormal category). Cardiologist’s interpretations will also be summarized in a shift table to 
determine the number and percentage of subjects with ECG results classified as normal or 
abnormal at scheduled post-Baseline visits relative to the same classification at the Baseline 
visit. The shifts from Baseline to overall post-Baseline worst interpretation will also be 
presented. For the by-visit shift summary, the denominator is the number of subjects with 
non-missing cardiologist’s interpretation at Baseline and the given visit for the given 
treatment group. For the summaries of shift from Baseline to the overall post-Baseline worst 
interpretation, the denominator is the number of subjects with non-missing Baseline and at 
least 1 post-Baseline cardiologist’s interpretation for the given treatment group.  
14.3.7.2.4 
Data Listings 
All data, including machine-read Baseline results, will be listed. A listing of all PCI values 
will be provided. This listing will include all observations for those subjects and parameters 
for which at least one PCI value (including Baseline) was observed. 
14.3.8 Physical Examination 
Physical examination is performed at Screening, Baseline, Week 4, and Week 8/ET visits.  
Physical examination results (normal, abnormal, and not done) at Baseline, Week 4, and 
Week 8/ET will be summarized in a frequency table by body system and visit. 
14.3.9 Suicidality 
14.3.9.1 
C-SSRS 
The C-SSRS will be administered if the subject, in the Investigator’s judgement, is able to 
reliably complete it. Otherwise, the GCAS will be administered and used thereafter in the 
study. 
The event counts and the number and percentage of subjects reporting any post-Baseline 
suicidal ideation (wish to be dead; non-specific active suicidal thoughts; active suicidal 
ideation with any methods (not plan) without intent to act; active suicidal ideation with some 
intent to act, without specific plan; active suicidal ideation with specific plan and intent), 
suicidal behavior (preparatory acts or behavior; aborted attempt; interrupted attempt; actual 
attempt; suicide), or suicidality (any suicidal ideation or behavior) will be tabulated. 


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The event counts and the number and percentage of subjects reporting any post-Baseline 
non-suicidal self-injurious behavior will also be tabulated. 
For calculating the percentages, the denominator will be the number of subjects with at least 
one post-Baseline C-SSRS assessment within each treatment group. 
14.3.9.2 
GCAS 
The number and percentage of subjects within each GCAS rating will be summarized using 
the clinician rating. The number and percentage of subjects reporting any post-Baseline rating 
of 3 or 4 will be tabulated. For these analyses, the denominator for calculating percentages is 
the number of subjects with at least one post-Baseline GCAS assessment within each 
treatment group.  
Subject and study partner/caregiver ratings will not be summarized but will be included in 
data listings. 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable. 
16 UNBLINDED INTERIM ANALYSES 
16.1 General Procedure 
One or more unblinded IAs of data from subjects who have exited the study (completed with 
or without enrolling into the open-label extension, or terminated early) may be conducted in 
order to support safety and efficacy evaluations for regulatory submissions. Subjects who 
have exited the study will only be unblinded and analyzed if  all other subjects in the same 
randomization block have also exited the study.  
The analyses planned for an unblinded IA will align with the purpose of the regulatory 
submission. Study subjects, study partners/caregivers, Investigators, raters, and site personnel 
will remain blinded to subject treatment assignments until all subjects have completed the 
study and the clinical database is locked. The distribution of unblinded subject’s treatment 
assignments within Acadia will be restricted. Further details regarding the restricted 
distribution of treatment assignments, IA results, and unblinding procedures will be specified 
in an IA Unblinding Plan.  
16.2 Interim Analysis 1 
The database lock for the first interim analysis (IA-1) occurred on December 13, 2019 (under 
version 1 of the SAP), and included data from 288 subjects whose last visit occurred on or 
before December 2, 2019. Data from these subjects may be used as a pre COVID-19 


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comparison group for selected safety and efficacy endpoints, in order to assess the potential 
impact of COVID-19 on the final study results. 
17 DATA MONITORING/REVIEW COMMITTEE 
An independent Data and Safety Monitoring Board (DSMB) will review interim and final 
safety data including AE and SAE data. The DSMB will be independent of the sponsor and 
the Investigators, and can recommend terminating the study early based on the safety review. 
An Independent Statistical Group (ISG), not affiliated with the Sponsor, will serve as a 
centralized communication gateway for data queries and additional data analyses/requests 
between the Sponsor and the DSMB. 
For DSMB safety reviews, the  treatment codes will be released to the ISG statistician who 
will be responsible for producing unblinded statistical outputs, and for providing these 
outputs to DSMB members using a secure method. The Sponsor and Investigators will 
remain blinded until the official unblinding of the database at the end of the study, except as 
described in Section 16. The outputs presented to DSMB members will include, but are not 
limited to, summaries of AEs, SAEs, deaths, laboratory measurements, ECGs, and vital signs. 
The DSMB will also be provided with SAEs and deaths reported in ACP-103-047, the 
open-label extension study for eligible subjects who complete ACP-103-046. 
Additional details regarding the roles and responsibilities of the DSMB members and ISG, 
and planned frequency of meetings, are specified in the DSMB Charter. 
In addition, blinded safety data will be monitored throughout the study and blinded aggregate 
safety reports will be produced and reviewed approximately quarterly. 
18 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS software 
(SAS Institute Inc., Cary, North Carolina) on a suitably qualified and validated environment. 
Linear mixed effects models will be fit using the PROC MIXED procedure. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Added DRP, AD, ADP, and Other subgroups, statistical tests for treatment comparisons of 
efficacy and secondary safety variables, and data handling related to Ukraine geopolitical 
conflict. 


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20 REFERENCES 
1. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic, March 2020; updated May 14, 2020. 
2. EMA Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic, March 2020. 
3. Yan X., Su G. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions, Statistics in Biopharmaceutical Research 2020; Vol. 2, No. 3, 
329-335. 


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21 APPENDICES 
21.1 Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original version 
 
24 July 2019 
2.0 
Updated to include handling of 
analyses related to COVID-19  
 
26 May 2020 
3.0 
In alignment with Protocol 
Amendment 7 changes were 
made to indicate that 
exploratory efficacy data from 
interim analyses conducted in 
this study may also be evaluated 
in order to support regulatory 
submissions. 
 
06 March 2021 
4.0 
Add subgroup analyses, nominal 
p-values for selected outputs, 
added anti-dementia use as a 
factor in CGI-S and CGI-I 
MMRM models, and Ukraine 
data handling. 
 
23 May 2022