A Double-blind, Placebo-controlled, Relapse Prevention Study of Pimavanserin for the Treatment of Hallucinations and Delusions Associated With Dementia-related Psychosis
Phase: PHASE3
Conditions: Dementia-related Psychosis
Sponsor: ACADIA Pharmaceuticals Inc.

Official Title: A Double-blind, Placebo-controlled, Relapse Prevention Study of 
Pimavanserin for the Treatment of Hallucinations and Delusions Associated With 
Dementia-related Psychosis  
NCT Number: NCT03325556 
Document Date: 16 Aug 2018 

 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 1 of 100 
 
 
CLINICAL STUDY PROTOCOL 
 
A Double-blind, Placebo-controlled, Relapse Prevention Study of 
Pimavanserin for the Treatment of Hallucinations and Delusions Associated 
With Dementia-related Psychosis 
 
Protocol Number: ACP-103-045 
Amendment 1 
 
EudraCT Number: 2017-002227-13 
 
Original Protocol Date: 1 June 2017 
Protocol Version 1.1 Date: 5 July 2017 
Protocol Amendment 1 Date: 16 August 2018 
 
 
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-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 3 of 100 
DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of GCP (International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use [ICH] Guidelines E6 and E2a]); as described in 21 CFR 
parts 50, 54, 56, 312, and 812; 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-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 4 of 100 
PROTOCOL SYNOPSIS 
Sponsor: ACADIA Pharmaceuticals Inc. 
Name of Investigational Product: Pimavanserin 
Indication: Treatment of hallucinations and delusions associated with dementia-related 
psychosis 
Protocol Title: A Double-blind, Placebo-controlled, Relapse Prevention Study of 
Pimavanserin for the Treatment of Hallucinations and Delusions Associated With Dementia-
related Psychosis 
Protocol Number: ACP-103-045 
EudraCT Number: 2017-002227-13 Phase: 3 
Primary Objective 
 To evaluate relapse prevention in 
subjects with dementia-related 
psychosis treated with pimavanserin 
compared to placebo 
Primary Endpoint 
 Time from randomization to relapse in the 
double-blind period 
Key Secondary Objective 
 To evaluate the time to discontinuation 
of the study for any reason in subjects 
with dementia-related psychosis 
treated with pimavanserin compared to 
placebo 
Key Secondary Endpoint 
 Time from randomization to discontinuation 
from the double-blind period for any reason 
Exploratory Objectives 
 To evaluate the benefit of 
pimavanserin compared to placebo in 
the following domains in subjects with 
dementia-related psychosis who have 
been stabilized on pimavanserin 
therapy: 
o symptoms of hallucinations and 
delusions 
o clinical global impressions 
o caregiver burden 
o daytime sleepiness 
o quality of life 
Exploratory Endpoints 
 Change from double-blind Baseline on the 
following: 
o Scale for the Assessment of Positive 
Symptoms-Hallucinations+Delusions 
(SAPS-H+D) score 
o SAPS Hallucinations domain score 
o SAPS Delusions domain score 
o Clinical Global Impression-Severity 
(CGI-S)-dementia-related psychosis 
o Zarit Burden Interview (ZBI) score 
o Karolinska Sleepiness Scale (KSS) score 
o EQ-5D-5L score 
o Clinical Global Impression-Improvement 
(CGI-I)-dementia-related psychosis  

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 5 of 100 
Safety Objective 
 To evaluate the safety and tolerability 
of pimavanserin compared to placebo 
in subjects with dementia-related 
psychosis who have been stabilized on 
pimavanserin therapy 
Safety Endpoints 
 Treatment-emergent adverse events (TEAEs) 
 Serious adverse events (SAEs) 
 Withdrawals due to adverse events (AEs) 
 Potentially clinically important changes in 
other safety assessments 
 Global Clinician Assessment of Suicidality 
(GCAS) score 
 Mini-Mental State Examination (MMSE) 
score 
 Extrapyramidal Symptom Rating Scale A 
(ESRS-A) score 
Pharmacokinetic Objectives 
 To characterize the pharmacokinetics 
(PK) of pimavanserin in subjects with 
dementia-related psychosis 
 To assess the pharmacokinetic/ 
pharmacodynamic (PK/PD) 
relationship using safety and efficacy 
endpoints in subjects with dementia-
related psychosis 
Pharmacokinetic Endpoints 
 Plasma concentration of pimavanserin and 
AC-279 
 Pimavanserin PK parameters using a 
population PK approach 
 PK/PD using appropriate PK/PD analysis 
methods 
Number of 
Study Sites 
Approximately 95 study sites will participate in this study. 
Number of 
Subjects Planned 
This study will enroll approximately 356 subjects in order to randomize 
approximately 178 subjects with dementia-related psychosis who meet 
response criteria. 
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 at Visit 1 (Screening), unless 
specified otherwise. 
Inclusion Criteria: 
1. Is a male or female ≥50 and ≤90 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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 6 of 100 
3. Meets criteria for All-cause Dementia according to NIA-AA 
guidelines (Appendix A) 
4. Meets clinical criteria for one of the following disorders, with or 
without cerebrovascular disease (CVD): 
a. Dementia associated with Parkinson’s disease  
(Appendix B) 
b. Dementia with Lewy bodies (Appendix C) 
c. Possible or probable Alzheimer’s disease (Appendix A) 
d. Frontotemporal degeneration spectrum disorders, 
including possible or probable: 
 Behavioral variant frontotemporal dementia 
(Appendix D) 
 Progressive supranuclear palsy (Appendix E) 
 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 and ≤24 
6. Has sufficient verbal and written ability to understand and 
answer questions and comply with procedures, with corrective 
measures such as hearing aids and reading glasses if necessary, 
and is willing and able to participate in all scheduled evaluations 
and complete all required tests 
7. Has had psychotic symptoms for at least 2 months 
8. Has all of the following scores at Visit 1 (Screening) and Visit 2 
(open-label Baseline): 
a. SAPS-H+D total score ≥10; AND 
b. CGI-S ≥4 (moderately ill); AND 
c. SAPS-H+D global item (H7 or D13) score ≥4 (marked) 
9. 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 
10. 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. Is fluent in the local language in which study 
assessments will be administered 
c. Agrees to participate in study assessments and provides 
written consent to participate in the study 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 7 of 100 
11. Can come to the clinic for study visits with a study 
partner/caregiver 
12. Has an MRI or CT scan of the brain (completed within past 
3 years) taken during or subsequent to the onset of dementia. If 
not available, a non-contrast brain MRI or non-contrast head CT 
must be done during screening. 
13. 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 (open-label 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 (open-label Baseline) 
14. If the subject is taking an antipsychotic medication at the time of 
screening, the antipsychotic 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). 
15. 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 (open-label Baseline), during the study, and 
1 month following completion of the study. Acceptable methods 
of birth control include the following: 
a. Condom, diaphragm, or cervical cap with spermicide 
b. Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
c. Intrauterine device (IUD) 
Exclusion Criteria: 
1. Is in hospice or end-of-life care 
2. Is confined to bed (subjects who can attend clinic visits using a 
wheelchair or other ambulatory assistive device are permitted) 
3. Requires skilled nursing care (procedures that can only be 
administered by a registered nurse or doctor, such as but not 
limited to, intravenous administration of medication, procedures 
related to insertion or care of suprapubic catheters, and 
nasopharyngeal/tracheostomy aspiration) 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 8 of 100 
4. Has psychotic symptoms that are primarily attributable to 
delirium, substance abuse, or a medical or psychiatric condition 
(e.g., schizophrenia, bipolar disorder, delusional disorder) other 
than dementia 
5. Has a current major depressive episode (within 3 months of 
Screening), according to the Diagnostic and Statistical Manual 
of Mental Disorders-Fifth Edition (DSM-5) criteria 
6. Has a Global Clinician Assessment of Suicidality (GCAS) 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 (open-label Baseline) 
7. Has evidence of a non-neurologic medical comorbidity or 
medication use that could substantially impair cognition 
8. Has a history of ischemic stroke within the last 12 months or 
any evidence of hemorrhagic stroke 
9. Has a known history of cerebral amyloid angiopathy (CAA), 
epilepsy, CNS neoplasm, or unexplained syncope 
10. Has atrial fibrillation unless adequately anticoagulated 
11. 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 [CCS] Angina Grading Scale) 
(Appendix K) 
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsade de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
12. Had a myocardial infarction within the 6 months prior to Visit 1 
(Screening) 
13. Has a known personal or family history or symptoms of long 
QT syndrome 
14. Has any of the following ECG results at Visit 1 (Screening) or 
Visit 2 (open-label 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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 9 of 100 
If the mean QTcF value from the set of ECGs done at Screening 
is prolonged 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. 
15. Has a heart rate <50 beats per minute. If bradycardia is 
secondary to iatrogenic or treatable causes and these causes are 
addressed, a heart rate assessment can be repeated during the 
screening period. 
16. Has a significant unstable medical condition that could interfere 
with subject’s ability to complete the study or comply with 
study procedures 
17. Has severe renal impairment, severe or medically significant 
impairment of hepatic function, and/or a clinically significant 
laboratory abnormality that in the judgment of the Investigator 
or Medical Monitor will interfere with the conduct or 
interpretation of safety or efficacy evaluations in the study 
18. Has one of the following screening laboratory results: 
a. Platelets ≤75,000/mm3 
b. Hemoglobin ≤9.5 g/dL if male, or ≤8.5 g/dL if female 
c. Neutrophils, absolute ≤1000/mm3 
d. Aspartate aminotransferase (AST) >2×upper limit of 
normal 
e. Alanine aminotransferase (ALT) >2×upper limit of 
normal 
f. Creatinine ≥2 mg/dL 
g. Hemoglobin A1c (HbA1c) ≥8.5% 
h. Abnormal free thyroxine (T4) 
i. Vitamin B12 deficiency 
Laboratory testing may be repeated during Screening at the 
discretion of the Medical Monitor.  
19. Has a history of a positive test result for HIV or hepatitis C 
20. 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) 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 10 of 100 
21. Requires treatment with a medication or other substance that is 
prohibited by the protocol 
22. Has a body mass index (BMI) <18.5 kg/m2 or known 
unintentional weight loss ≥7% of body weight over past 6 
months 
23. 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 or barbituates 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 
(open-label Baseline). The repeat Screening test must be 
negative for them to participate in the study. The presence of 
benzodiazepines, marijuana (THC), or opiates may not exclude 
the subject from the study. 
24. 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 1 (Screening) OR has 
participated in a clinical trial for disease-modifying therapy 
within 6 months of Visit 1 
25. Has previously been enrolled in any prior clinical study with 
pimavanserin or is currently taking pimavanserin 
26. Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
27. Is an employee or is a family member of an employee of 
ACADIA Pharmaceuticals Inc. 
28. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study for any reason 
Test Product, 
Dose, and 
Administration 
Pimavanserin 34 mg (provided as 2×17 mg tablets), 20 mg (provided as 
2×10 mg tablets), and matching placebo (2×placebo tablets [size- and 
color-matched to pimavanserin tablets]) 
Planned Duration 
of Treatment 
The duration of participation for individual study subjects will be up to 
47 weeks, consisting of a screening period of up to 5 weeks; an open-
label period of 12 weeks; a double-blind period of up to 26 weeks; and 
an approximately 4-week safety follow-up period.  
The study discontinuation date is defined as the day on which the 
Sponsor notifies sites that the study is ending (for example, in the event 
of a positive interim analysis or after 75 adjudicated relapses). The 
study completion date is defined as the day on which the last subject 
completes the last scheduled assessment (i.e., safety follow-up). 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 11 of 100 
Study Design 
This is a Phase 3, prospective, double-blind, placebo-controlled, 
multicenter, relapse prevention study in subjects with dementia-related 
psychosis. 
This study will have 4 treatment periods (Figure S–1): 
 Screening period (3-35 days) 
 Open-label period (12 weeks) 
 Double-blind period (up to 26 weeks) 
 Safety follow-up period (approximately 4 weeks) 
The schedule of assessments is provided in Table S–1 and Table S–2. 
Screening Period (3-35 Days) 
During the screening period, subjects will be assessed for study 
eligibility and prohibited medications will be discontinued when 
medically appropriate. Subjects and partner/caregivers will also receive 
a standardized psychosocial therapy training. 
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. 
Open-label Period (12 Weeks) 
During the open-label period, eligible subjects will begin receiving 
pimavanserin 34 mg once daily (QD) beginning at Week 0 (open-label 
Baseline); subsequent clinic visits will occur at Weeks 2, 4, 8, and 12. 
Dose adjustments are permitted at scheduled or unscheduled visits until 
Week 4. After Week 4, the subject’s dose will remain fixed at either 
34 mg or 20 mg once daily. 
To enter the double-blind period, eligible subjects must meet the 
following response criteria at Weeks 8 and 12: 
 Subject experiences a ≥30% reduction (improvement) from Week 0 
(open-label Baseline) on the SAPS-H+D Total Score AND 
 Subject has a CGI-I score of 1 (very much improved) or 2 (much 
improved), relative to Week 0 (open-label Baseline) 
A subject who does not meet response criteria at Week 8 and 12 will be 
withdrawn from study drug and enter the safety follow-up period of the 
study. 
Double-blind Period (up to 26 Weeks) 
Randomization will occur at the double-blind Baseline visit (Week 12). 
Subjects will be randomly assigned 1:1 to continue their pimavanserin 
dose (34 mg or 20 mg) or matching placebo. Randomization will be 
stratified by: 
1. Most likely dementia subtype or most prominent cause of 
dementia: 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 12 of 100 
 Alzheimer's disease or frontotemporal dementia spectrum 
disorders 
 Vascular dementia 
 Parkinson’s disease dementia or dementia with Lewy 
bodies 
2. Region 
The protocol-defined relapse criteria for dementia-related psychosis are: 
 Subject experiences a ≥30% increase (worsening) from Week 12 
(double-blind Baseline) on the SAPS-H+D Total Score AND has a 
CGI-I score of 6 (much worse) or 7 (very much worse), relative to 
the double-blind Baseline; OR 
 Subject is treated with an antipsychotic (other than pimavanserin) 
for dementia-related delusions and/or hallucinations; OR 
 Subject stops study drug or withdraws from study for lack of 
efficacy (as reported by the subject or study partner/caregiver) or 
the Investigator discontinues study drug due to lack of efficacy; OR 
 Subject is hospitalized for worsening dementia-related psychosis 
Relapse criteria will be assessed weekly for the first 2 weeks after 
randomization (Weeks 13 and 14), every 2 weeks until Week 26, and 
every 4 weeks through Week 38. Relapse criteria may also be evaluated 
at unscheduled visits. Any subject who meets any of the relapse criteria 
after randomization will be withdrawn from study drug and enter the 
safety follow-up period of the study. 
All subjects who discontinue the study between randomization and 
Week 38 should complete an ET visit, if possible, and an independent 
adjudication committee (IAC) will review those cases that occurred 
before the study discontinuation date to determine if protocol-defined 
relapse criteria were met.  
Safety Follow-up Period (Approximately 4 Weeks) 
Approximately 4 weeks after the last dose of study drug, subjects will 
have a safety follow-up telephone call visit. 
The Sponsor will provide investigative sites with 3 months of after-
study assistance to transition subjects to standard of care therapy after 
their participation in the study. 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board will review safety 
information on a regular basis throughout the study. 
Pharmacokinetic 
Assessments 
During the open-label period, PK samples will be collected at Weeks 0, 
8, and 12. 
During the double-blind period, PK samples will be collected at Weeks 
13, 22, and 38/EOT. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 13 of 100 
Pharmacokinetic samples will also be collected, if possible, at any ET 
visit or the visit immediately following any SAE or following an AE 
leading to discontinuation. 
For all PK samples (scheduled and unscheduled), the dates and times of 
administration of the last 3 doses of study drug should be recorded, as 
well as the date and time of the sample draw. For samples collected 
from subjects who experience any SAE or experience an AE leading to 
discontinuation, the date and time of the last dose of study drug prior to 
the SAE or AE should also be recorded. 
Optional 
Pharmacogenomic 
Assessments 
A blood sample will be collected at Visit 2 (open-label Baseline) or later 
from consenting subjects for potential future pharmacogenomics 
analyses (where local regulations permit). 
Data for genetic analyses will be anonymized, as is the customary 
approach according to Good Clinical Practice (GCP). 
Sample Size 
Calculations 
The sample size calculation was based on the following assumptions: a 
placebo relapse event rate of 60% over 26 weeks; a pimavanserin 
relapse event rate of 35% over 26 weeks; a dropout rate of 25% over 
26 weeks; an overall two-sided alpha level of 0.05; use of a one-sided 
(0.025) O’Brien-Fleming stopping boundary to adjust for a single 
interim analysis that will be performed when one half of the total 
planned number of post-randomization relapse events have occurred; 
and a power of 90%. The total number of post-randomization relapse 
events required at the final analysis is 75 and the calculated sample size 
is 89 in each of the two treatment groups (giving a total of 178). 
Study enrollment will be closed when approximately 178 subjects have 
been randomized in the double-blind period or when 75 adjudicated 
post-randomization relapse events have occurred. In the event that the 
randomization rate is lower than anticipated and/or the relapse event 
rate is lower than anticipated, the number enrolled and randomized may 
be increased up to a maximum of 400 randomized subjects in order to 
observe 75 post-randomization relapse events. 
An interim efficacy analysis of the primary efficacy endpoint will be 
performed after 38 adjudicated relapse events have occurred. The study 
may be terminated early if the interim analysis results meet prespecified 
stopping criteria For example, if there are exactly 38 relapse events at 
the interim analysis, the significance level will be 0.0054. If the study is 
not stopped early and the final analysis includes exactly 75 relapse 
events (including the 38 events from the interim analysis), the 
significance level for the final analysis will be 0.0479. The actual 
significance levels to be used at the interim and final analyses will be 
calculated based on the actual number of events observed. The interim 
efficacy analysis will be performed by an independent statistician. 
Investigators, subjects, and Sponsor personnel will remain blinded 
throughout the study. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 14 of 100 
Statistical 
Methods 
The primary efficacy analysis will be based on the Intent-to-treat (ITT) 
population, defined as all randomized subjects. The time from 
randomization to relapse in the double-blind period will be compared 
between treatment groups using a Cox regression model with effects for 
treatment group, dementia subtype, and region. The nominal p-value, 
hazard ratio, and 95% confidence interval will be reported. Subjects 
who discontinue early or complete the study without having 
experienced a relapse event will be censored at the time of last 
assessment for relapse. The key secondary endpoint of time from 
randomization to discontinuation from the double-blind period for any 
reason (other than termination of the study by the Sponsor) will be 
analyzed using the same methodology as for the primary endpoint. 
A hierarchical testing procedure will be used to control the overall 
type I error rate for the primary and key secondary endpoints. 
Exploratory Efficacy Analyses 
All exploratory efficacy endpoints will be summarized by treatment 
group using descriptive statistics. For all exploratory SAPS endpoints, 
CGI-S, ZBI, KSS, and EQ-5D-5L; the change from double-blind 
Baseline will be analyzed using mixed model repeated measures 
(MMRM). The independent variables in the model will include the 
following: treatment group (pimavanserin or placebo), visit, treatment 
by visit interaction, double-blind Baseline score, double-blind Baseline 
score by visit interaction, designated dementia subtype , and region. 
CGI-I will be analyzed using an MMRM model with the following 
independent variables: treatment group (pimavanserin or placebo), visit, 
treatment by visit interaction, double-blind Baseline CGI-S score, 
double-blind Baseline CGI-S score by visit interaction, designated 
dementia subtype , and region. 
The treatment comparisons will be based on the difference in least 
squares means and will be tested at a two-sided alpha level of 0.05. The 
double-blind Baseline score is defined as the last value prior to the first 
dose of double-blind study drug. 
In addition to the MMRM analyses described above, last-observation-
carried-forward analyses will also be performed. 
Descriptive summaries of efficacy endpoints, including the number and 
percent of subjects meeting response criteria, will be provided for the 
open-label period. 
Safety Analyses 
All safety results will be summarized using descriptive statistics. 
Separate summaries will be provided for the open-label and double-
blind periods. The double-blind summaries will be presented by 
treatment group. Adverse events will be classified into standard 
terminology using the Medical Dictionary for Regulatory Activities. 
Adverse events may also be categorized into categories of special 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 15 of 100 
interest. Treatment-emergent AEs (TEAEs), TEAEs leading to 
discontinuation, TEAEs related to study drug, TEAEs by maximum 
severity, serious TEAEs, and serious TEAEs related to study drug will 
all be summarized. Other TEAEs of special interest may also be 
summarized. 
Descriptive statistics for ECG, vital signs, GCAS, MMSE, ESRS-A 
total score and all subscales, and clinical laboratory parameters, 
including change from Baseline when applicable, will be tabulated by 
treatment group and timepoint. Additionally, categorical analyses will 
be conducted on the incidence of subjects with prolonged QTc intervals 
and changes in QTc intervals in accordance with International Council 
for Harmonisation (ICH) guidelines. The incidence of clinically 
significant changes in selected laboratory parameters will also be 
summarized. 
Pharmacokinetic Analyses 
Plasma concentration data for pimavanserin and AC-279 will be listed 
and summarized using descriptive statistics. 
If data allow, population PK and PK/PD analyses will be performed to 
further characterize the PK profile and exposure response relationship 
of pimavanserin using measures of safety and efficacy parameters. The 
results of population PK and PK/PD modeling will be presented in a 
separate report. Investigators, subjects, and Sponsor personnel will 
remain blinded to plasma concentration data from the double-blind 
period until the unblinding of the clinical database at the end of the 
study. 
Date 
16 August 2018 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
Page 16 of 100 
Figure S–1 
Schematic of Study Design for ACP-103-045 
 
 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 17 of 100 
Table S–1 
Schedule of Assessments for ACP-103-045: Screening and Open-
label Period 
 
Screening 
Open-label Period 
Visit week 
-5 to 0 
0 
2 
4 
8 
12a 
Allowable visit window (# days) 
 
 
±3 
±3 
±3 
+7 
Visit Number 
1 
2 
3 
4 
5 
6 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria assessment 
X 
X 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
Mini-Mental State Examination 
X 
X 
X 
X 
X 
X 
MRI or CTb 
X 
 
 
 
 
 
Psychosocial therapy training 
X 
 
 
 
 
 
Physical and neurological examinations 
X 
X 
 
 
 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
12-lead electrocardiogramc 
X 
X 
X 
 
 
X 
Clinical laboratory tests 
X 
X 
 
 
 
X 
Pregnancy testd 
X 
X 
 
 
 
X 
SAPS-H+D 
X 
X 
X 
X 
X 
X 
Clinical Global Impression-Improvemente 
 
 
X 
X 
X 
X 
Clinical Global Impression-Severity 
X 
X 
X 
X 
X 
X 
Zarit Burden Interviewf 
 
X 
 
 
 
X 
Karolinska Sleepiness Scale 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
X 
Assessment for response criteria 
 
 
 
 
X 
X 
Assessment for concomitant medications 
X 
X 
X 
X 
X 
X 
Global Clinician Assessment of Suicidality 
X 
X 
X 
X 
X 
X 
Extrapyramidal Symptom Rating Scale A 
 
X 
 
 
 
X 
Assessment for adverse events 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample collectiong 
 
X 
 
 
X 
X 
Pharmacogenomic sample collectionh 
 
X 
 
 
 
 
Drug dispensation 
 
X 
X 
X 
X 
Xi 
Drug return and accountability 
 
 
X 
X 
X 
X 
Randomization 
 
 
 
 
 
X 
Footnotes for Table S–1 on next page 
Abbreviations: CT=computed tomography; MRI=magnetic resonance imaging; SAPS-H+D=Scale for the 
Assessment of Positive Symptoms, Hallucinations and Delusions subscales 
Note: All efforts should be made to complete each visit in a single day. In the event of a split visit, the CGI-
S/CGI-I and the SAPS H+D must be completed on the same day. 
Note: When a subject is found to be appropriate for discontinuation from the trial, the visit during which this is 
determined should immediately be converted to an ET visit (as described in Table S–2) and all procedures 
and assessments listed in the schedule of events for the ET visit (Week 38/EOT; Visit 17/ET) should be 
completed (additional details provided in Section 4.4). Safety follow-up should be completed as scheduled. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 18 of 100 
For additional details on study procedures, see Section 6.  
a 
Visit 6 (Week 12) will serve as both the final visit of the open-label period and the Baseline visit of the 
double-blind period (Table S–2). 
b 
A non-contrast brain MRI or non-contrast head CT will be completed if the subject has not had a CT or 
MRI scan completed (a) within the past 3 years AND (b) during or subsequent to the onset of dementia. 
c 
The ECG will be completed in triplicate at Visit 1 (Screening). A single ECG will be completed at all other 
visits. 
d 
A pregnancy test (serum at Visit 1 and urine at all other visits) 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. 
e 
The CGI-I should be scored relative to Visit 2, the subject’s open-label Baseline. 
f 
The ZBI should only be administered to study partners/caregivers who are family members. 
g 
Pharmacokinetic samples will also be collected, if possible, at any ET visit (Table S-2) or the visit 
immediately following any SAE or following an AE leading to discontinuation. 
h 
A separate informed consent (and assent, if applicable) must be given for the pharmacogenomic component 
of the study. This consent may be obtained at any time during the study. If informed consent is given in time 
for sample collection at Visit 2, a pre-dose sample should be collected at Visit 2. If informed consent for 
pharmacogenomics is not given in time for sample collection at Visit 2, a sample may be collected any time 
after informed consent for pharmacogenomics is given. 
i 
Blinded study drug will be dispensed after randomization at Visit 6 (Week 12). 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
Page 19 of 100 
Table S–2 
Schedule of Assessments for ACP-103-045: Double-blind Period 
Visit week 
13 
14 
16 
18 
20 
22 
24 
26 
30 
34 
38/EOT 
42 
Allowable visit window (# days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
+7 
+3 
Visit Number 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17/ET 
18 
Visit Type (Clinic [C] or Telephone [T]) 
C 
C 
C 
C 
T 
C 
T 
C 
C 
C 
C 
T 
Mini-Mental State Examination 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Physical and neurological examinations 
 
 
 
 
 
X 
 
 
 
 
X 
 
Vital signs and weight 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
12-lead electrocardiogram 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Clinical laboratory tests 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Pregnancy testa 
 
 
 
 
 
 
 
X 
 
 
X 
 
SAPS-H+D 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Clinical Global Impression-Improvementb 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Clinical Global Impression-Severity 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Zarit Burden Interviewc 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Karolinska Sleepiness Scale 
 
 
 
X 
 
 
 
X 
 
 
X 
 
EQ-5D-5L 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Assessment for protocol-defined relapse criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment for concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Global Clinician Assessment of Suicidality 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Extrapyramidal Symptom Rating Scale A 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Assessment for adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample collectiond 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Drug dispensation 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Drug return and accountability 
Xe 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Footnotes and abbreviations for Table S–2 on next page 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
Page 20 of 100 
Abbreviations: EOT=end-of-treatment; ET=early termination; SAPS-H+D=Scale for the Assessment of Positive Symptoms, Hallucinations and Delusions 
subscales 
For additional details on study procedures, see Section 6. 
Note: All efforts should be made to complete each visit in a single day. In the event of a split visit, the CGI-S/CGI-I and the SAPS H+D must be completed on 
the same day. 
Note: When a subject is found to be appropriate for discontinuation from the trial, the visit during which this is determined should immediately be converted to 
an ET visit (as described in Table S–2) and all procedures and assessments listed in the schedule of events for the ET visit (Week 38/EOT; Visit 17/ET) 
should be completed (additional details provided in Section 4.4). Safety follow-up should be completed as scheduled. 
a 
A urine 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. 
b 
The CGI-I should be scored relative to Visit 6 (Week 12), the subject’s double-blind Baseline. 
c 
The ZBI should only be administered to study partners/caregivers who are family members. 
d 
Pharmacokinetic samples will also be collected, if possible, at the visit immediately following any SAE or following an AE leading to discontinuation. 
e 
Only drug accountability will be completed at this visit. 

Study ACP-103-045
Final Version: 1.0
Clinical Study Protocol Amendment 1
Date: 16 August 2018
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 21 of 100
Table of Contents
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR .................................................................................... 3 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
Table of Contents ..................................................................................................................... 21 
List of Tables ............................................................................................................................ 25 
List of Figures .......................................................................................................................... 25 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 26 
1 INTRODUCTION ............................................................................................................. 28 
1.1 
Background Information ................................................................................................ 28 
1.2 
Investigational Product .................................................................................................. 30 
1.3 
Previous Clinical Experience ......................................................................................... 30 
1.3.1 
Parkinson’s Disease Psychosis Program ................................................................... 30 
1.3.2 
Alzheimer’s Disease Psychosis ................................................................................. 31 
1.4 
Study Rationale.............................................................................................................. 33 
2 STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 35 
2.1 
Primary Objective .......................................................................................................... 35 
2.1.1 
Primary Endpoint ....................................................................................................... 35 
2.2 
Key Secondary Objective .............................................................................................. 35 
2.2.1 
Key Secondary Endpoint ........................................................................................... 35 
2.3 
Exploratory Objectives .................................................................................................. 35 
2.3.1 
Exploratory Endpoints ............................................................................................... 35 
2.4 
Safety Objective ............................................................................................................ 36 
2.4.1 
Safety Endpoints ........................................................................................................ 36 
2.5 
Pharmacokinetic Objectives .......................................................................................... 36 
2.5.1 
Pharmacokinetic Endpoints ....................................................................................... 36 
3 STUDY DESCRIPTION ................................................................................................... 36 
3.1 
Overview of Study Design ............................................................................................ 36 
3.2 
Screening Period (3-35 Days)........................................................................................ 37 
3.3 
Open-label Period (12 Weeks) ....................................................................................... 37 
3.4 
Double-blind Period (up to 26 Weeks) .......................................................................... 38 
3.5 
Safety Follow-up Period (Approximately 4 Weeks)...................................................... 38 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ......................................... 39 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 22 of 100 
4.1 
Subject Selection and Withdrawal ................................................................................. 39 
4.2 
Inclusion Criteria ........................................................................................................... 39 
4.3 
Exclusion Criteria .......................................................................................................... 41 
4.4 
Subject Withdrawal or Termination ............................................................................... 44 
4.5 
Prior and Concomitant Therapy..................................................................................... 46 
4.5.1 
Permitted, Restricted, and Prohibited Medications ................................................... 46 
5 INVESTIGATIONAL PRODUCT .................................................................................... 47 
5.1 
Investigational Product Description .............................................................................. 47 
5.1.1 
Formulation, Appearance, Packaging, and Labeling ................................................. 47 
5.1.2 
Product Storage and Stability .................................................................................... 48 
5.1.3 
Dosing and Administration ........................................................................................ 48 
5.1.4 
Dose Adjustments/Modifications/Delays .................................................................. 48 
5.1.5 
Method of Assigning Subjects to Treatment Groups ................................................. 48 
5.1.6 
Blinding ..................................................................................................................... 48 
5.1.7 
Study Drug Compliance ............................................................................................ 49 
5.1.8 
Overdose .................................................................................................................... 49 
5.2 
Investigational Product Accountability Procedures ....................................................... 49 
6 STUDY PROCEDURES ................................................................................................... 50 
6.1 
Screening Assessments .................................................................................................. 50 
6.1.1 
Mini-Mental State Examination ................................................................................ 50 
6.1.2 
Medical History and Demographics .......................................................................... 50 
6.1.3 
Brain Imaging ............................................................................................................ 50 
6.1.4 
Psychosocial Therapy – Non-pharmacologic Intervention Prior to 
Randomization ........................................................................................................... 50 
6.2 
Efficacy Assessments..................................................................................................... 51 
6.2.1 
Scale for the Assessment of Positive Symptoms – Hallucinations and Delusions .... 51 
6.2.2 
Clinical Global Impression – Severity and Clinical Global Impression –
Improvement Scales ................................................................................................... 51 
6.2.3 
Zarit Burden Interview .............................................................................................. 51 
6.2.4 
Karolinska Sleepiness Scale ...................................................................................... 52 
6.2.5 
EQ-5D-5L .................................................................................................................. 52 
6.3 
Safety Assessments ........................................................................................................ 52 
6.3.1 
Physical and Neurological Examinations .................................................................. 52 
6.3.2 
Vital Signs .................................................................................................................. 52 
6.3.3 
Height, Weight and Body Mass Index ....................................................................... 52 
6.3.4 
Electrocardiograms .................................................................................................... 53 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 23 of 100 
6.3.5 
Global Clinician Assessment of Suicidality .............................................................. 53 
6.3.6 
Extrapyramidal Symptom Rating Scale ..................................................................... 53 
6.3.7 
Laboratory Evaluations .............................................................................................. 54 
6.3.8 
Safety Follow-up ....................................................................................................... 56 
6.4 
Pharmacokinetic Assessments ....................................................................................... 56 
6.4.1 
Pharmacogenomic Assessment .................................................................................. 57 
6.4.2 
Specimen Preparation, Handling, Storage, and Shipment ......................................... 57 
6.5 
Unscheduled Visits ........................................................................................................ 57 
7 ADVERSE EVENTS ......................................................................................................... 57 
7.1 
Specification of Safety Parameters ................................................................................ 57 
7.1.1 
Definition of Adverse Event ...................................................................................... 57 
7.1.2 
Definition of Serious Adverse Event ......................................................................... 58 
7.2 
Classification of an Adverse Event ................................................................................ 60 
7.2.1 
Severity of Event ....................................................................................................... 60 
7.2.2 
Relationship to Study Drug ....................................................................................... 60 
7.2.2.1 
Duration ................................................................................................................. 60 
7.2.2.2 
Frequency ............................................................................................................... 60 
7.2.2.3 
Action Taken with Study Drug .............................................................................. 61 
7.2.2.4 
Therapy .................................................................................................................. 61 
7.2.2.5 
Outcome ................................................................................................................. 61 
7.2.2.6 
Seriousness ............................................................................................................. 61 
7.2.3 
Definition of Unexpectedness .................................................................................... 61 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ............................... 61 
7.4 
Reporting Procedures .................................................................................................... 62 
7.4.1 
Adverse Event Reporting ........................................................................................... 62 
7.4.2 
Serious Adverse Event Reporting .............................................................................. 62 
7.4.3 
Reporting of Pregnancy ............................................................................................. 63 
7.4.4 
Reporting of Overdose ............................................................................................... 63 
8 CLINICAL MONITORING .............................................................................................. 63 
9 STATISTICAL METHODS AND DATA ANALYSIS ...................................................... 64 
9.1 
Statistical and Analytical Plans...................................................................................... 64 
9.2 
Statistical Hypotheses .................................................................................................... 64 
9.3 
Sample Size Determination ........................................................................................... 64 
9.4 
Subject Populations for Analysis ................................................................................... 65 
9.5 
Description of Statistical Methods ................................................................................ 65 
9.5.1 
Primary Efficacy Analyses ......................................................................................... 65 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 24 of 100 
9.5.2 
Key Secondary Analyses ........................................................................................... 66 
9.5.3 
Exploratory Efficacy Analyses .................................................................................. 66 
9.5.4 
Safety Analyses .......................................................................................................... 67 
9.5.5 
Pharmacokinetic Analyses ......................................................................................... 67 
9.5.6 
Data and Safety Monitoring Board ............................................................................ 67 
9.5.7 
Independent Adjudication Committee ....................................................................... 67 
9.5.8 
Planned Interim Analyses .......................................................................................... 68 
9.5.9 
Additional Subgroup Analyses .................................................................................. 68 
9.5.10 
Multiple Comparisons/Multiplicity ........................................................................... 69 
9.6 
Enrollment, Randomization, and Masking Procedures ................................................. 69 
9.6.1 
Breaking the Study Blind/Subject Code .................................................................... 69 
10 STUDY MANAGEMENT AND DATA COLLECTION .................................................. 70 
10.1 Data Collection and Management Responsibilities ....................................................... 70 
10.2 Source Documents ......................................................................................................... 70 
10.3 Case Report Forms ........................................................................................................ 70 
10.4 Confidentiality ............................................................................................................... 71 
10.5 Study Records Retention ............................................................................................... 71 
10.6 Protocol Exceptions and Deviations .............................................................................. 71 
10.7 Protocol Amendments.................................................................................................... 72 
11 STUDY MONITORING, AUDITING, AND INSPECTING............................................ 72 
11.1 Quality Control and Quality Assurance ......................................................................... 72 
12 ETHICAL CONSIDERATIONS ....................................................................................... 72 
12.1 Ethical Standard ............................................................................................................. 72 
12.2 Institutional Review Board/Ethics Committee .............................................................. 73 
12.3 Informed Consent Process ............................................................................................. 73 
12.3.1 
Consent and Other Informational Documents Provided to Subjects ......................... 74 
12.3.2 
Consent Procedures and Documentation ................................................................... 74 
13 PUBLICATION PLAN ...................................................................................................... 74 
14 CONFLICT OF INTEREST POLICY ............................................................................... 74 
14.1 Finance, Insurance, and Indemnity ................................................................................ 74 
15 LITERATURE REFERENCES ......................................................................................... 75 
16 APPENDICES ................................................................................................................... 79 
Appendix A 
NIA-AA Guidelines for All-cause Dementia and Alzheimer’s Disease.......... 79 
Appendix B 
Movement Disorder Society’s Task Force Clinical Diagnostic Criteria for 
Dementia Associated with Parkinson’s Disease ............................................. 82 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 25 of 100 
Appendix C 
Dementia with Lewy Bodies Consortium Clinical Diagnostic Criteria .......... 84 
Appendix D 
International Consensus Criteria for Behavioral Variant Frontotemporal 
Dementia ......................................................................................................... 86 
Appendix E 
Neuroprotection and Natural History in Parkinson Plus Syndromes 
Diagnostic Criteria for Progressive Supranuclear Palsy ................................. 88 
Appendix F 
Corticobasal Degeneration Diagnostic Criteria ............................................... 89 
Appendix G 
VASCOG Criteria for Vascular Dementia ....................................................... 90 
Appendix H 
Prohibited and Restricted Medications ........................................................... 92 
Appendix I 
Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 ................................................... 96 
Appendix J 
New York Heart Association Classification of Heart Failure .......................... 98 
Appendix K 
Canadian Cardiovascular Society Angina Grading Scale ............................... 99 
Appendix L 
Predictors Composing the PHASES Aneurysm Rupture Risk Score ............ 100 
 
List of Tables 
Table S–1 
Schedule of Assessments for ACP-103-045: Screening and Open-label 
Period ............................................................................................................... 17 
Table S–2 
Schedule of Assessments for ACP-103-045: Double-blind Period.................. 19 
Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer's 
Disease, Parkinson's Disease, and Lewy Body Dementia ............................... 29 
Table 1–2 
NPI-NH Psychosis Score Percent Responder Analysis – Full Analysis Set 
– Week 6 (Day 43) ........................................................................................... 32 
Table 6–1 
Safety Laboratory Evaluations ......................................................................... 56 
 
List of Figures 
Figure S–1 
Schematic of Study Design for ACP-103-045 ................................................. 16 
 
 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 26 of 100 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AC-279 
N-desmethyl-pimavanserin, major metabolite of pimavanserin 
AD 
Alzheimer’s disease 
AE 
adverse event 
bvFTD 
behavioral variant FTD 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CNS 
central nervous system 
CT 
computed tomography 
DLB 
dementia with Lewy bodies 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition  
DSMB 
Data and Safety Monitoring Board 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end-of-treatment 
ESRS-A 
Extrapyramidal Symptom Rating Scale A 
ET 
early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FTD 
frontotemporal dementia 
GCAS 
Global Clinician Assessment of Suicidality 
GCP 
Good Clinical Practice 
IAC 
independent adjudication committee 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
Intent-to-treat 
KSS 
Karolinska Sleepiness Scale 
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 
NINDS 
National Institute of Neurological Disorders and Stroke 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 27 of 100 
Term 
Definition 
NPI-NH 
Neuropsychiatric Inventory-Nursing Home Version 
PDD 
Parkinson’s disease dementia 
PDP 
Parkinson’s disease psychosis 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PP 
Per-protocol 
QD 
once daily 
SAE 
serious adverse event 
SAPS 
Scale for the Assessment of Positive Symptoms 
SAPS-H+D 
SAPS Hallucinations and Delusions subscales 
SAS® 
Statistical Analysis System 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment emergent adverse event 
VaD 
vascular dementia 
VASCOG 
International Society for Vascular Behavioral and Cognitive 
Disorders 
ZBI 
Zarit Burden Interview 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 28 of 100 
1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol and International Council for Harmonisation (ICH) Good 
Clinical Practice Guideline (GCP). All key personnel (all individuals responsible for the 
design and conduct of this study) have completed or will complete human subjects protection 
training. 
1.1 
Background Information 
Dementia is a syndrome with core symptoms, most notably a decline in cognitive function, 
but with a variety of other manifestations that are rarely confined to one subtype. Alzheimer’s 
disease (AD) is the most common and well-known cause of dementia. Most studies of 
dementia-related psychosis focus on AD. However the various subtypes of dementia have 
more features in common than they have distinguishing them. The current study allows 
enrollment of subjects with psychosis associated with the most common subtypes of 
dementia: AD, vascular dementia (VaD), Parkinson’s disease dementia (PDD), dementia with 
Lewy bodies (DLB), and the frontotemporal dementia (FTD)-spectrum disorders (including 
behavioral variant FTD [bvFTD], progressive supranuclear palsy [PSP], and corticobasal 
degeneration [CBD]). These subtypes of dementia overlap greatly in 1) their clinical 
presentation and nosology and in 2) their pathological findings on autopsy 
(Brenowitz et al. 2017). 
Psychosis is common in dementia. It is typical of DLB, very common in AD (Table 1–1) and 
occurs, although to a lesser degree, in VaD and the FTD-spectrum disorders. It is also a 
frequent complication of PDD. The psychosis in most dementias 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 PDD. 
Patients with psychosis who had a clinical diagnosis of AD are often found on autopsy to 
have Lewy bodies or vascular lesions in addition to amyloidopathy (Fischer et al. 2016; 
Kim et al. 2017). Thus, the premortem diagnosis of dementia subtype may be less important 
when treating psychosis in dementia than the confirmation that the psychotic symptoms are 
associated with dementia and not with another psychiatric or medical illness such as 
schizophrenia or delirium. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 29 of 100 
Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer's 
Disease, Parkinson's Disease, and Lewy Body Dementia 
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 
 
Dementia-related psychosis differs substantially from schizophrenia, mania with psychotic 
features, major depressive disorder with psychotic features, and other major mental illnesses. 
Jeste and Finkel (2000) laid out the ways in which the psychosis of AD is a different 
syndrome than the psychosis of schizophrenia in elderly patients. The same comparison can 
be made between dementia-related psychosis in general and psychosis in schizophrenia. 
Because of these differences, the assessment of psychosis in dementia is focused on a narrow 
set of symptoms (e.g., hallucinations and delusions) distinct from schizophrenia 
(Jeste and Finkel 2000; Cohen-Mansfield and Golander 2011). There is evidence that 
psychotic features in AD, DLB, and PDD 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 and Sweet 2010; Creese et al. 2014). 
Treatment of dementia-related psychosis represents an area of high unmet need. Clinical 
experience and clinical trial data with atypical antipsychotics have consistently shown 
treatment effects across the spectrum of all neurodegenerative dementias (Devanand et al. 
2012 supplementary material; DeDeyn et al. 1999; Devanand et al. 1998; Katz et al. 1999; 
Street et al. 2000). However, the CATIE-AD study concluded that the adverse effects of 
risperidone, olanzapine, and quetiapine offset their advantages in efficacy. Although the 
atypical antipsychotic drugs were more effective than placebo, adverse effects limited their 
overall effectiveness. The authors stated that use of these agents may be restricted to patients 
who have few or no side effects and for whom benefits can be discerned (Schneider et al. 2006). 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 30 of 100 
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 United States 
(US) for the treatment of hallucinations and delusions associated with Parkinson’s disease 
psychosis (PDP). 
Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 5-hydroxytryptamine (5-HT [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 be effective in treating hallucinations and delusions associated 
with dementia-related psychosis and may have added benefits with regard to overall 
tolerability relative to other antipsychotic agents. 
In this study, subjects will be asked to take pimavanserin tablets once daily as an oral 
formulation. 
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 Alzheimer’s disease 
psychosis (ADP) and schizophrenia. The PDP program and Phase 2 ADP study are reviewed 
below. A more complete discussion of these studies, as well as the schizophrenia program, is 
available in the pimavanserin 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 
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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 31 of 100 
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. 
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 subjects with ADP 
(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 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 34 mg 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 (0.49) years. The mean (SE) 
Baseline NPI-NH psychosis score for all FAS subjects was 9.8 (0.39) with comparable mean 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 32 of 100 
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) treatment effect for pimavanserin compared 
with placebo. Prespecified subgroup analyses for the primary endpoint at Week 6 confirmed 
the observation of efficacy with the enhancement of the efficacy signal and effect size 
observed in the overall population. Similarly, prespecified responder analyses showed 
significant increases in responder rates at Week 6 in the pimavanserin treatment group 
compared to placebo. On the endpoint of mean change in NPI-NH psychosis score at 
Week 12, pimavanserin generally maintained the achieved improvement on psychosis 
observed at the Week 6 primary endpoint, but the statistical difference from placebo was not 
maintained due to apparent improvement in the placebo group between Weeks 6 and 12. 
NPI-NH psychosis score responder analyses also demonstrate the significant and clinically 
relevant treatment effect of pimavanserin 34 mg compared with placebo in subjects with 
ADP. Furthermore, defining responder as either a 30% or greater improvement or a 50% or 
greater improvement from Baseline NPI-NH psychosis score showed a significantly greater 
proportion of responders in the pimavanserin group (Table 1–2). 
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 non-response 
 
With respect to safety, pimavanserin 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 SAEs reported in pimavanserin group (16.7%) than in the placebo group 
(11.0%). A review of individual SAEs revealed a similar distribution of Medical Dictionary 
for Regulatory Activities (MedDRA) preferred terms between the two treatment groups with 
no clusters or common underlying mechanisms identified. However, there were fewer 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 33 of 100 
discontinuations due to AEs in the pimavanserin group (8.9%) compared with the placebo 
group (12.1%). 
The most frequently reported AEs in the pimavanserin group were fall (23.3%), urinary tract 
infection (22.2%), and agitation (21.1%). 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. 
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 (8.5%) 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 
As discussed above, dementia-related psychosis is an area of high unmet need. Psychosis is a 
common occurrence in the disease evolution of patients with dementia. The reported 
prevalence of psychotic symptoms in patients with dementia ranges from ~20% to 90%. In 
spite of the significant medical need, currently there is no pharmacologic treatment approved 
for dementia-related psychosis. Atypical antipsychotics are frequently used to treat this 
disorder despite significant safety concerns about their use in this population. 
Psychotic symptoms found in the various subtypes of dementia are similar to each other and 
quite different from the psychotic symptoms of major mental illnesses such as schizophrenia. 
The clinical management of dementia-related psychosis does not differ among subtypes of 
dementia. The subtypes of dementia themselves overlap both clinically and pathologically. 
Most patients with dementia receive their diagnosis without further specification of dementia 
subtype. 
Clinical data presented above show pimavanserin to be effective in the acute treatment of 
hallucinations and delusions in subjects with PDP. Positive Phase 2 data in an acute treatment 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 34 of 100 
setting in subjects with ADP are also described above. The purpose of this study is to evaluate 
relapse prevention in a broad group of subjects with dementia-related psychosis. 
The relapse prevention design of this study maximizes the duration of exposure to a 
potentially effective treatment and minimizes the duration of exposure to ineffective 
treatment (Temple and Ellenberg 2000; US FDA 2012a). Enrichment is a powerful design to 
demonstrate a drug’s effectiveness using clinical trial data. Furthermore, it is an efficient 
design to determine whether a new drug is safe and effective for its intended use in a 
population with serious illness that lacks good treatment alternatives. 
The advantages of the relapse prevention design stem from the fact that all subjects will 
receive open-label pimavanserin treatment upon entering the study and that there will be 
specific criteria for randomization based on an individual’s response to flexible-dose, open-
label treatment. Subjects who do not respond positively to pimavanserin treatment during the 
open-label period will be withdrawn from the study. Subjects who respond positively (are 
stabilized according to predefined criteria) will be randomized in a double-blind fashion to 
receive either pimavanserin or placebo. During this double-blind period, subjects who meet 
protocol-defined criteria for relapse will be immediately withdrawn from study drug and 
enter the safety follow-up period of the study. Subjects who continue to benefit from 
treatment may continue treatment for the duration of the double-blind period (26 weeks). 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 35 of 100 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to evaluate relapse prevention in subjects with 
dementia-related psychosis treated with pimavanserin compared to placebo. 
2.1.1 
Primary Endpoint 
The primary endpoint for this study will be time from randomization to relapse in the double-
blind period. 
2.2 
Key Secondary Objective 
The key secondary objective of this study is to evaluate the time to discontinuation of the 
study for any reason in subjects with dementia-related psychosis treated with pimavanserin 
compared to placebo. 
2.2.1 
Key Secondary Endpoint 
The key secondary endpoint for this study will be time from randomization to discontinuation 
from the double-blind period for any reason. 
2.3 
Exploratory Objectives 
The exploratory objectives are to evaluate the benefit of pimavanserin compared to placebo 
in the following domains in subjects with dementia-related psychosis who have been 
stabilized on pimavanserin therapy: 
 symptoms of hallucinations and delusions 
 clinical global impressions 
 caregiver burden 
 daytime sleepiness 
 quality of life 
2.3.1 
Exploratory Endpoints 
The exploratory endpoints for this study are as follows: 
 Change from double-blind Baseline on the following: 
o Scale for the Assessment of Positive Symptoms-Hallucinations+Delusions 
(SAPS-H+D) score 
o SAPS Hallucinations domain score 
o SAPS Delusions domain score 
o Clinical Global Impression-Severity (CGI-S)-dementia-related psychosis 
o Zarit Burden Interview (ZBI) score 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 36 of 100 
o Karolinska Sleepiness Scale (KSS) score 
o EQ-5D-5L score 
o Clinical Global Impression-Improvement (CGI-I)-dementia-related psychosis 
2.4 
Safety Objective 
The safety objective for this study is to evaluate the safety and tolerability of pimavanserin 
compared to placebo in subjects with dementia-related psychosis who have been stabilized on 
pimavanserin therapy. 
2.4.1 
Safety Endpoints 
The safety endpoints for this study are as follows: 
 Treatment-emergent adverse events (TEAEs) 
 Serious adverse events (SAEs) 
 Withdrawals due to adverse events (AEs) 
 Potentially clinically important changes in other safety assessments 
 Global Clinician Assessment of Suicidality (GCAS) score 
 Mini-Mental State Examination (MMSE) score 
 Extrapyramidal Symptom Rating Scale A (ESRS-A) score 
2.5 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for this study are as follows: 
 To characterize the PK of pimavanserin in subjects with dementia-related psychosis 
 To assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship using safety and 
efficacy endpoints in subjects with dementia-related psychosis 
2.5.1 
Pharmacokinetic Endpoints 
The PK endpoints for this study are as follows: 
 Plasma concentration of pimavanserin and AC-279 
 Pimavanserin PK parameters using a population PK approach 
 PK/PD using appropriate PK/PD analysis methods 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This is a Phase 3, prospective, double-blind, placebo-controlled, multicenter, relapse 
prevention study in subjects with dementia-related psychosis. Approximately 95 study sites 
will participate in this study. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 37 of 100 
The duration of participation for individual study subjects will be up to 47 weeks, consisting 
of a screening period of up to 5 weeks; an open-label period of 12 weeks; a double-blind 
period of up to 26 weeks; and an approximately 4-week safety follow-up period.  
The study discontinuation date is defined as the day on which the Sponsor notifies sites that 
the study is ending (for example, in the event of a positive interim analysis or after 75 
adjudicated relapse events). The study completion date is defined as the day on which the last 
subject completes the last scheduled assessment (i.e., safety follow-up). A study schematic is 
provided in Figure S–1. 
3.2 
Screening Period (3-35 Days) 
During the screening period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued when medically appropriate. Subjects and 
partner/caregivers will also receive a standardized psychosocial therapy training. 
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. 
3.3 
Open-label Period (12 Weeks) 
During the open-label period, eligible subjects will begin receiving pimavanserin 34 mg once 
daily (QD) beginning at Week 0 (open-label Baseline). Subsequent clinic visits will occur at 
Weeks 2, 4, 8, and 12. Dose adjustments are permitted at scheduled or unscheduled visits 
until Week 4. After Week 4, the subject’s dose will remain fixed at either 34 mg or 20 mg 
once daily. 
To enter the double-blind period, eligible subjects must meet the following response criteria 
at Weeks 8 and 12: 
 Subject experiences a ≥30% reduction (improvement) from Week 0 (open-label Baseline) 
on the SAPS-H+D Total Score AND 
 Subject has a CGI-I score of 1 (very much improved) or 2 (much improved), relative to 
Week 0 (open-label Baseline) 
A subject who does not meet response criteria at Weeks 8 and 12 will be withdrawn from 
study drug and enter the safety follow-up period of the study. 
Pharmacokinetic samples will be collected at Weeks 0, 8, and 12. Pharmacokinetic samples 
will also be collected, if possible, at any ET visit or the visit immediately following any SAE 
or following an AE leading to discontinuation. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 38 of 100 
3.4 
Double-blind Period (up to 26 Weeks) 
Randomization will occur at the double-blind Baseline visit (Week 12). Subjects will be 
randomly assigned 1:1 to continue their pimavanserin dose (34 mg or 20 mg) or matching 
placebo. 
The protocol-defined relapse criteria for dementia-related psychosis are designed to identify 
subjects with an impending relapse or relapse of psychosis: 
 Subject experiences a ≥30% increase (worsening) from Week 12 (double-blind Baseline) 
on the SAPS-H+D Total Score AND has a CGI-I score of 6 (much worse) or 7 (very 
much worse), relative to the double-blind Baseline1; OR 
 Subject is treated with an antipsychotic (other than pimavanserin) for dementia-related 
delusions and/or hallucinations; OR 
 Subject stops study drug or withdraws from study for lack of efficacy, (as reported by the 
subject or study partner/caregiver) or the Investigator discontinues study drug due to lack 
of efficacy; OR 
 Subject is hospitalized for worsening dementia-related psychosis 
Relapse criteria will be assessed weekly for the first 2 weeks after randomization (Weeks 13 
and 14), every 2 weeks until Week 26, and every 4 weeks through Week 38. Relapse criteria 
may also be evaluated at unscheduled visits. Any subject who meets any of the relapse 
criteria after randomization will be withdrawn from study drug and enter the safety follow-up 
period of the study. 
All subjects who discontinue the study between randomization and Week 38 should complete 
an ET visit, if possible, and an independent adjudication committee (IAC) will review those 
cases that occurred before the study discontinuation date to determine if protocol-defined 
relapse criteria were met.  
Pharmacokinetic samples will be collected at Weeks 13, 22, and 38/EOT. Pharmacokinetic 
samples will also be collected, if possible, at any ET visit or the visit immediately following 
any SAE or following an AE leading to discontinuation. 
3.5 
Safety Follow-up Period (Approximately 4 Weeks) 
Approximately 4 weeks after the last dose of study drug, subjects will have a safety 
follow-up telephone call visit. 
                                                 
1 For subjects with a Week 12 (double-blind baseline) SAPS H+D total score of “0”, any increase in the 
SAPS H+D total score at any visit after Week 12 will satisfy the criteria for a >30% increase (worsening). 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 39 of 100 
The Sponsor will provide investigative sites with 3 months of after-study assistance to 
transition subjects to standard of care therapy after their participation in the study. 
4 SUBJECT ELIGIBILITY 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 at Visit 1 (Screening), unless specified otherwise. Subject eligibility criteria 
will be verified prior to Visit 2 (open-label Baseline). This study will randomize up to 
approximately 178 subjects with dementia-related psychosis who meet response criteria 
(Section 3.3). 
In order to participate in the optional pharmacogenomics component of the study, subjects 
must sign a separate pharmacogenomics informed consent form (ICF), indicating their 
willingness to have their DNA sample stored for future use. Refusal to consent for this 
component does not exclude a subject from participation in the clinical study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s post-enrollment participation in the study, it is discovered 
that the subject did not meet all eligibility criteria, she or he will be discontinued, unless the 
discontinuation presents an unacceptable medical risk. The justification to allow the subject 
to continue in the study 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. 
Subjects who screen fail will be allowed to rescreen with the permission of the Medical 
Monitor, provided the screen failure was due to a temporary condition that subsequently 
resolved. 
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 ≥50 and ≤90 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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 40 of 100 
b. The subject must provide written (if capable) informed assent 
3. Meets criteria for All-cause Dementia according to NIA-AA guidelines (Appendix A) 
4. Meets clinical criteria for one of the following disorders, with or without 
cerebrovascular disease (CVD): 
a. Dementia associated with Parkinson’s disease (Appendix B) 
b. Dementia with Lewy bodies (Appendix C) 
c. Possible or probable Alzheimer’s disease (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 and ≤24 
6. Has sufficient verbal and written ability to understand and answer questions and 
comply with procedures, with corrective measures such as hearing aids and reading 
glasses if necessary, and is willing and able to participate in all scheduled evaluations 
and complete all required tests 
7. Has had psychotic symptoms for at least 2 months 
8. Has all of the following scores at Visit 1 (Screening) and Visit 2 (open-label 
Baseline): 
a. SAPS-H+D total score ≥10; AND 
b. CGI-S ≥4 (moderately ill); AND 
c. SAPS-H+D global item (H7 or D13) score ≥4 (marked) 
9. 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 
10. 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. Is fluent in the local language in which study assessments will be administered 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 41 of 100 
c. Agrees to participate in study assessments and provides written consent to 
participate in the study 
11. Can come to the clinic for study visits with a study partner/caregiver 
12. Has an MRI or CT scan of the brain (completed within past 3 years) taken during or 
subsequent to the onset of dementia. If not available, a non-contrast brain MRI or 
non-contrast head CT must be done during screening. 
13. 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 (open-label 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 (open-label Baseline) 
14. If the subject is taking an antipsychotic medication at the time of screening, the 
antipsychotic 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). 
15. 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 (open-label Baseline), during the 
study, and 1 month following completion of the study. Acceptable methods of birth 
control include the following:  
a. Condom, diaphragm, or cervical cap with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
c. Intrauterine device (IUD) 
4.3 
Exclusion Criteria 
1. Is in hospice or end-of-life care 
2. Is confined to bed (subjects who can attend clinic visits using a wheelchair or other 
ambulatory assistive device are permitted) 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 42 of 100 
3. Requires skilled nursing care (procedures that can only be administered by a 
registered nurse or doctor, such as but not limited to, intravenous administration of 
medication, procedures related to insertion or care of suprapubic catheters, and 
nasopharyngeal/tracheostomy aspiration) 
4. Has psychotic symptoms that are primarily attributable to delirium, substance abuse, 
or a medical or psychiatric condition (e.g., schizophrenia, bipolar disorder, delusional 
disorder) other than dementia 
5. Has a current major depressive episode (within 3 months of Screening), according to 
the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) 
criteria 
6. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 or 4 based on 
Investigator’s assessment of behavior within 3 months prior to Visit 1 (Screening) or 
since-last-visit at Visit 2 (open-label Baseline) 
7. Has evidence of a non-neurologic medical comorbidity or medication use that could 
substantially impair cognition 
8. Has a history of ischemic stroke within the last 12 months or any evidence of 
hemorrhagic stroke 
9. Has a known history of cerebral amyloid angiopathy (CAA), epilepsy, CNS 
neoplasm, or unexplained syncope 
10. Has atrial fibrillation unless adequately anticoagulated therapy 
11. 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 
[CCS] Angina Grading Scale) (Appendix K) 
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsade de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
12. Had a myocardial infarction within the 6 months prior to Visit 1 (Screening) 
13. Has a known personal or family history or symptoms of long QT syndrome 
14. Has any of the following ECG results at Visit 1 (Screening) or Visit 2 (open-label 
Baseline): 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 43 of 100 
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 is <120 ms 
ii QTcF >450 ms, if QRS duration ≥120 ms 
If the mean QTcF value from the set of ECGs done at Screening is prolonged 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.  
15. Has a heart rate <50 beats per minute. If bradycardia is secondary to iatrogenic or 
treatable causes and these causes are addressed, a heart rate assessment can be 
repeated during the screening period. 
16. Has a significant unstable medical condition that could interfere with subject’s ability 
to complete the study or comply with study procedures 
17. Has severe renal impairment, severe or medically significant impairment of hepatic 
function, and/or a clinically significant laboratory abnormality that in the judgment of 
the Investigator or Medical Monitor will interfere with the conduct or interpretation of 
safety or efficacy evaluations in the study 
18. Has one of the following screening laboratory results: 
a. Platelets ≤75,000/mm3 
b. Hemoglobin ≤9.5 g/dL if male, or ≤8.5 g/dL if female 
c. Neutrophils, absolute ≤1000/mm3 
d. Aspartate aminotransferase (AST) >2×upper limit of normal 
e. Alanine aminotransferase (ALT) >2×upper limit of normal 
f. Creatinine ≥2 mg/dL 
g. Hemoglobin A1c (HbA1c) ≥8.5% 
h. Abnormal free thyroxine (T4) 
i. Vitamin B12 deficiency 
Laboratory testing may be repeated during Screening at the discretion of the Medical 
Monitor. 
19. Has a history of a positive test result for HIV or hepatitis C 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 44 of 100 
20. 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) 
21. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
22. Has a body mass index (BMI) <18.5 kg/m2 or known unintentional weight loss ≥7% 
of body weight over past 6 months 
23. 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 or barbituates 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 (open-label Baseline). The repeat Screening test must be 
negative for them to participate in the study. The presence of benzodiazepines, 
marijuana (THC), or opiates may not exclude the subject from the study. 
24. 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 1 
(Screening) OR has participated in a clinical trial for disease-modifying therapy 
within 6 months of Visit 1 
25. Has previously been enrolled in any prior clinical study with pimavanserin or is 
currently taking pimavanserin 
26. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
27. Is an employee or is a family member of an employee of ACADIA Pharmaceuticals Inc. 
28. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
for any reason 
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 45 of 100 
Subjects may be discontinued or withdrawn from the study for a number of reasons, 
including, but not limited to, those listed below: 
 Relapse of hallucinations and delusions associated with dementia-related psychosis 
 Adverse event 
 Death 
 Lost to follow-up 
 Non-compliance with study drug 
 Use of prohibited medications 
 Physician decision 
 Pregnancy 
 Protocol violation 
 Study terminated by Sponsor 
 Subject withdraws consent 
 Other 
When a subject is found to be appropriate for discontinuation from the trial, the visit during 
which this is determined should immediately be converted to an ET visit (as described in 
Table S–2) and all procedures and assessments listed in the schedule of events for the ET visit 
(Week 38/EOT; Visit 17/ET) should be completed. Safety follow-up should be completed as 
scheduled. 
For subjects who discontinue from the trial between visits, every reasonable effort should be 
made to complete Visit 17/early termination (ET) and the safety follow-up period. 
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 46 of 100 
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–2. Unless the subject 
has withdrawn consent to be contacted for this study, every reasonable effort will be made to 
complete the 4-week 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 or ethical 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 
Lifetime antipsychotic use and response is to be recorded. All other medications used up to 
24 weeks prior to Visit 2 through Visit 18 (telephone visit) or ET are to be recorded. 
In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator (unless the subject is receiving treatment for a medical emergency). 
4.5.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications, as specified in Appendix H and 
Appendix I, should be followed between Visit 1 (Screening) and Visit 17/ET. Medications 
that can prolong QT interval are prohibited (or restricted if approved by the Medical Monitor 
or appropriate designee) as specified in Appendix H. These appendices do not constitute an 
exhaustive list and any questions regarding prohibited and restricted medications or the use of 
medications that could interfere with study conduct should be discussed with the Medical 
Monitor or appropriate designee. 
If a subject is on a restricted or prohibited medication at screening, the medication should be 
adjusted or discontinued only if it is determined by the Investigator to be clinically 
appropriate (e.g., if the subject's symptoms are not well-controlled or if the subject cannot 
tolerate the current medication). 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 47 of 100 
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 are discovered to 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 remain in the study will be made by the 
Sponsor/Medical Monitor, with medical input from the Investigator, and will be documented. 
If the subject is allowed to remain in the study, this will be reported as a major protocol 
deviation and not a waiver. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 34 mg (provided as 2×17 mg tablets), 
pimavanserin 20 mg (provided as 2×10 mg tablets), and matching placebo (2×placebo 
tablets). Placebo tablets will be size- and color-matched to the pimavanserin tablets 
corresponding to the subject’s dose level at the end of the open-label period. Tablets will be 
administered orally as a single dose once daily (QD). 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 17 mg and 10 mg tablets and matching placebo 
tablets. 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin tablets include the active 
compound (pimavanserin) 
 
 
. The 
drug product is formulated with standard pharmaceutical excipients at 17 mg strength (20 mg 
of pimavanserin tartrate) and 10 mg strength (11.8 mg of pimavanserin tartrate). 
Pimavanserin treatment consists of 2 tablets once daily for oral administration. 
Placebo tablets contain all of the same excipients as pimavanserin 17 mg and 10 mg tablets 
but do not contain any pimavanserin. 
Pimavanserin and placebo tablets are manufactured under current Good Manufacturing 
Practice compliance. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 48 of 100 
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 at 15°C to 30°C (59°F to 86°F) (see US 
Pharmacopeial Controlled Room Temperature) 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 clinic; study drug kits will then be 
dispensed to the subject to take home. Each daily dose consists of 2 individual tablets that 
should be taken together. Subjects should be instructed to take 2 whole tablets, orally, once 
each day. Subjects should be instructed to not crush the tablets. The tablets may be taken with 
or without food. 
5.1.4 
Dose Adjustments/Modifications/Delays 
The first dose of open-label pimavanserin 34 mg will be taken at the beginning of the open-
label period (Week 0 [Visit 2]). Pimavanserin will continue daily at this dose level for at least 
the first week of treatment. After the first week, if the subject is unable to tolerate the 34 mg 
dose, the dose may be decreased to 20 mg at any study visit (scheduled or unscheduled) until 
Week 4 (Visit 4). If the dose is decreased to 20 mg it may later be increased to 34 mg based 
on investigator judgment at any study visit (scheduled or unscheduled) until Week 4 (Visit 4). 
After Week 4 (Visit 4), the dose of study drug will remain fixed at either 34 mg or 20 mg 
once daily. 
When the dose is adjusted, subjects should be instructed to return all treatment kits, blister 
cards, and unused tablets from the previous dose level before the next dose level is dispensed. 
Dose adjustments will be recorded in the interactive response technology (IRT) system. 
5.1.5 
Method of Assigning Subjects to Treatment Groups 
At Week 12 (Visit 6), subjects who meet response criteria (Section 3.3) will be randomized in 
a 1:1 ratio to either continue receiving pimavanserin at the current dose level or to receive 
matched placebo. 
5.1.6 
Blinding 
All subjects will receive open-label pimavanserin (34 mg or 20 mg) during the open-label 
period of the study. 
Treatment assignment during the double-blind period will be double-blind such that neither 
the subjects, study partners/caregivers, Sponsor personnel who oversee the study, nor the 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 49 of 100 
Investigator and study personnel will know which treatment is assigned to each subject. 
Details regarding medical emergency unblinding procedures are provided in Section 9.6.1. 
5.1.7 
Study Drug Compliance 
If a subject misses 1 dose of study drug, he or she should not take an extra dose the next day. 
5.1.8 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol. It must be reported, irrespective of outcome even if toxic effects 
were not observed. All events of overdose are to be captured on the overdose form 
(Section 7.4.4) as protocol deviations. 
5.2 
Investigational Product Accountability Procedures 
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, used, and returned for each subject to assure the health 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 (except Visit 7), any unscheduled visit where a dose change occurs, and any ET 
visits. At Visit 7 (Week 13), the amount of study drug product used since Visit 6 (Week 12) 
will be recorded but no study drug should be returned to the Investigator and no new 
treatment kits will be dispensed to the subject. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor representative who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 
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 
ACADIA. 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. 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received and comparing it with the accompanying material shipping form. The 
Investigator or designee will verify the accuracy of the information on the form, sign and date 
it, and provide a copy of it to the Sponsor or designee. Any study drug supplied is for use in 
this study only and should not be used for any other purpose. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 50 of 100 
6 STUDY PROCEDURES 
Study-specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table S–1 for screening and the open-label period and as described 
in Table S–2 for the double-blind period. Every reasonable effort should be made to complete 
the required procedures and evaluations at the designated visits and times. 
6.1 
Screening Assessments 
6.1.1 
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. 
6.1.2 
Medical History and Demographics 
A complete medical history will be obtained from each potential subject, including details of 
the subject’s psychiatric history and treatment (including prior use of and response to 
antipsychotic medication), details of the subject’s dementia diagnosis and treatment 
(including date of onset of cognitive impairment), and details of any neurologic diagnosis and 
treatment. 
Subjects may be asked to provide pharmacy or medical records to substantiate the medication 
history (Section 4.5). 
Demographic information, including date of birth, sex, race, and ethnicity will be recorded as well 
(as allowed by local regulations). Any new medical condition reported after the ICF has been 
signed will be captured as an AE. 
6.1.3 
Brain Imaging 
A non-contrast brain MRI or non-contrast head CT will be completed if the subject has not 
had a CT or MRI scan completed (a) within the past 3 years AND (b) during or subsequent to 
the onset of dementia. If the Investigator believes a brain MRI with contrast or a head CT 
with contrast is clinically warranted, such a study may be done. The purpose of the scan is to 
evaluate criteria excluding a clinically significant CNS abnormality (Section 4). 
6.1.4 
Psychosocial Therapy – Non-pharmacologic Intervention Prior to 
Randomization 
During the screening period, the designated study partner/caregiver will receive instruction 
for engaging in a structured psychosocial interaction with the subject. This psychological 
intervention is intended to aid the subject and caregiver in managing the subject’s 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 51 of 100 
neuropsychiatric symptoms. Study partners/caregivers will be instructed on the therapy by 
trained site personnel and will have weekly supportive telephone contacts. It is recommended 
to conduct the intervention at a frequency of 5 times per week (minimum of 3 times per 
week) for the duration of the screening period. 
6.2 
Efficacy Assessments 
6.2.1 
Scale for the Assessment of Positive Symptoms – Hallucinations and Delusions 
The SAPS (Andreasen 1984) was designed to measure positive psychotic symptoms. Positive 
symptoms include hallucinations, delusions, abnormalities in language and behavior, and 
disordered thought processes. The SAPS Hallucinations and Delusions subscales (SAPS-H+D) 
will be administered in this study. The Hallucinations and Delusions subscales consist of 
20 items, including global ratings of severity both of hallucinations (H7) and of delusions 
(D13), respectively. 
All efforts should be made to complete each visit in a single day. In the event of a split visit, the 
CGI-S/CGI-I and the SAPS H+D must be completed on the same day. 
6.2.2 
Clinical Global Impression – Severity and Clinical Global Impression –
Improvement Scales 
The CGI-S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s hallucinations and delusions at the time of assessment using the Investigator’s 
judgment and past experience with subjects who have the same disorder (i.e., dementia-
related psychosis) (Guy 1976). 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s hallucinations and delusions at the time of assessment, relative to the symptoms at 
Baseline (relative to open-label Baseline for response criteria and relative to double-blind 
Baseline for relapse criteria). 
All efforts should be made to complete each visit in a single day. In the event of a split visit, the 
CGI-S/CGI-I and the SAPS H+D must be completed on the same day. 
6.2.3 
Zarit Burden Interview 
The Zarit Burden Interview (ZBI) was designed to assess the stress experienced by caregivers 
of patients with dementia (Zarit et al. 1980). The ZBI will be administered as an interview. 
The interview consists of 22 statements reflecting how people sometimes feel when taking 
care of another person. The statements are phrased as questions for the family member study 
partner/caregiver to indicate how often they feel the way described in the statement. 
Responses are Never, Rarely, Sometimes, Quite Frequently, and Nearly Always. When the 
study partner/caregiver is not a family member, this scale will not be completed. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 52 of 100 
6.2.4 
Karolinska Sleepiness Scale 
The Karolinska Sleepiness Scale (KSS) is a 9-item, self-reported subjective measure of a 
subject’s level of drowsiness (Åkerstedt and Gillberg 1990). Respondents must choose the 
statement that most accurately describes their level of sleepiness over the past few minutes. 
6.2.5 
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 study partner/caregiver (the proxy) is asked to rate subject's health-
related quality of life in their (the proxy’s) opinion. 
6.3 
Safety Assessments 
6.3.1 
Physical and Neurological Examinations 
A general physical examination will be conducted. The physical exam procedures will 
include the following organ systems: 
 Head, ears, eyes, nose, and throat 
 Skin 
 Cardiovascular 
 Respiratory 
 Abdomen 
 Genitourinary (optional) 
 Musculoskeletal 
 Lymph nodes 
In addition, a neurological exam (cranial nerves, motor, sensory, reflexes, gait, and 
coordination) will be conducted. 
6.3.2 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, sitting systolic and 
diastolic blood pressure, and pulse rate. The resting blood pressure should be measured after 
the subject has been sitting or supine for ≥5 minutes. 
6.3.3 
Height, Weight and Body Mass Index 
Height will be recorded in centimeters or in inches. 
Weight will be recorded in kilograms or in pounds. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 53 of 100 
Body mass index (BMI) 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. 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. All ECGs will be 
centrally read; the interpretation by the central cardiologist is considered the official 
interpretation. ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF and QTcB 
intervals) will be included and summarized in the subject's study records.  
The ECG will be completed in triplicate at Visit 1 (Screening) and as a single tracing at all 
other visits. The following conditions apply: 
 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. 
 If the mean QTcF value from the set of ECGs done at Screening is  prolonged  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. In this case, the repeat set of triplicate ECGs will be used in determination of 
subject eligibility. 
 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 
enrollment of the subject will not be considered a protocol deviation. 
6.3.5 
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 
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. 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. 
6.3.6 
Extrapyramidal Symptom Rating Scale 
The ESRS (Chouinard and Margolese 2005) was developed to assess drug induced 
movement disorders such as Parkinsonism, akathisia, dystonia and tardive dyskinesia with 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 54 of 100 
established reliability, validity and sensitivity. It has demonstrated excellent inter-rater 
reliability in idiopathic Parkinson’s disease (Chouinard et al. 1984). 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 treatment to monitor for any worsening in 
extrapyramidal symptoms or signs at scheduled visits. 
6.3.7 
Laboratory Evaluations 
The laboratory evaluations will include, but are not limited to, the following: 
 Clinical chemistry serum tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH) 
o Magnesium (Mg) 
 Mg should only be performed at Visit 1 (Screening) 
o Vitamin B12 
 Vitamin B12 should only be performed at Visit 1 (Screening) 
o HbA1c 
 HbA1c should only be performed at Visit 1 (Screening), Visit 6, and 
Visit 17/ET 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Thyroid stimulating hormone (TSH) and free T4 
 TSH should be performed only at Visit 1 (Screening) 
 Free T4 will be measured only if the TSH is abnormal 
o Lipid Panel 
 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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 55 of 100 
 If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done 
 Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
 Urinalysis 
o Color, clarity, blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, 
pH, leukocyte esterase, nitrite, microscopic analysis 
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. 
 Urine toxicity screen 
o Reasonable efforts should be made to collect a urine sample at all other scheduled 
visits as described in ‘Urinalysis’ above 
o In cases of positive drug screens, the Medical Monitor may request confirmatory 
testing of the sample  
o Subjects who test positive for amphetamines or barbituates 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 (open-label Baseline). The repeat Screening test must 
be negative for them to participate 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 visit. In addition, restrictions listed in 
Appendix H should be followed. 
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 56 of 100 
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, urine toxicity screen, and urine pregnancy test 
Visit 6 (Week 12) 
CHEM, CBC, UA, urine toxicity screen, and urine pregnancy test 
Visit 10 (Week 18) 
CHEM, CBC, and UA 
Visit 14 (Week 26) 
CHEM, CBC, UA, and urine pregnancy test 
Visit 17/ET (Week 38) 
CHEM, CBC, UA, and urine pregnancy test 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; 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. 
b 
Mg, TSH, and vitamin B12 tests are only required at Visit 1 (Screening) and an HbA1c test is only required 
at Visit 1 (Screening), Visit 6, and Visit 17/ET. 
 
6.3.8 
Safety Follow-up 
A 4-week safety follow-up telephone contact is to be completed for all subjects. Subjects will 
have the following completed via telephone approximately 4 weeks after the last dose of 
study drug: 
 Assessment of concomitant medications/treatments 
 Assessment of AEs 
6.4 
Pharmacokinetic Assessments 
Pharmacokinetic samples will be collected for measurement of concentrations of 
pimavanserin and its metabolite AC-279. 
When possible, an additional PK sample will be collected from subjects who experience any 
SAE or experience an AE leading to discontinuation as soon as possible after the occurrence 
of that event. 
For all PK samples (scheduled and unscheduled) the date and time of the last 3 doses of study 
drug, as well as the date and time of the sample draw, should be recorded. For samples 
collected from subjects who experience any SAE or experience an AE leading to 
discontinuation, the date and time of the last dose of study drug prior to the SAE or AE 
should also be recorded. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 57 of 100 
6.4.1 
Pharmacogenomic Assessment 
A single blood draw will be performed for subjects who have signed a separate 
pharmacogenomics consent form indicating their willingness to have their DNA sample 
stored for possible future genetic research related to pimavanserin or the indication(s) for 
which it is developed (where local regulations permit). Stored DNA samples and relevant 
clinical data will be made non-identifiable after the clinical study report has been issued. 
Personal identifiers will be removed and each study subject identifier will be replaced with a 
new number to limit the possibility of linking genetic data to a subject’s identity. 
The pharmacogenomic assessment is an optional component of the study requiring a separate 
informed consent, which may be obtained at any time during the study. The 
pharmacogenomic sample may be collected at any time following informed consent for the 
pharmacogenomic component of the study. 
6.4.2 
Specimen Preparation, Handling, Storage, and Shipment 
Investigators, subjects, and Sponsor personnel will remain blinded to pimavanserin plasma 
concentration data from the double-blind period until the unblinding of the clinical database 
at the end of the study. 
6.5 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following safety 
assessments generally should be recorded at each unscheduled visit: assessment of AEs, 
assessment of concomitant medications/treatments, and measurement of vital signs. The 
Investigator may perform any additional safety evaluations deemed by the Investigator to be 
clinically indicated. Relapse criteria may also be evaluated at unscheduled visits. 
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 2012b). 
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 58 of 100 
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 the open-label 
Baseline. 
 Overdose of either study drug (see Section 7.4.4) or concomitant medication without any 
signs or symptoms unless the subject is hospitalized for observation 
 Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred) 
 Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
 
Adverse events will be recorded from the time informed consent is obtained through 30 days 
after the last dose of study drug. 
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. 
Serious AEs occurring after the safety 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 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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 59 of 100 
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 that might have had an outcome of death had it 
occurred in a more severe form. 
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.  
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 60 of 100 
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 
may have been caused by the study drug 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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 61 of 100 
7.2.2.3 
Action Taken with Study Drug 
 Dose reduced: Study drug reduced 
 Dose increased: Study drug increased 
 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 
 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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 62 of 100 
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 MedDRA. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator as described above. 
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. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by ACADIA to the Regulatory Authorities is a regulatory requirement. 
Each Regulatory Authority has established a timetable for reporting SAEs based upon 
established criteria. 
Serious AEs and other reportable information must be reported within 24 hours of discovery 
to ACADIA or its designee. The SAE (initial and/or follow-up), pregnancy (Section 7.4.3), or 
overdose (Section 7.4.4) of study drug must be reported within 24 hours by completing the 
SAE, pregnancy, or overdose forms, as appropriate (details on how to report SAEs are 
provided in a separate study reference manual). 
At a minimum, events identified by ACADIA to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
institutional review board (IRB)/ethics committee (EC). For European Union member states, 
ACADIA 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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 63 of 100 
For this study, sites will complete the paper overdose, SAE, and/or pregnancy form (for 
initial and/or follow-up information), including available supporting documentation relevant 
to the event and send (within 24 hours of discovery) to the contact numbers and/or email 
designated on the SAE form provided to the sites. 
Subjects will be followed until Visit 17/ET for any SAEs and/or other reportable information 
or until such events have resolved or the Investigator, in conjunction with ACADIA, deems 
them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
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. Any 
female subject who becomes pregnant during the study will be followed through the first 
well-baby visit. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.4 
Reporting of Overdose 
Any overdose (Section 5.1.8) must be reported within 24 hours by completing the overdose 
form. Any AEs that are associated with the event and which meet the criteria for SAEs should 
also be reported via the SAE form. 
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 64 of 100 
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 unblinding for the interim analysis. 
9.2 
Statistical Hypotheses 
The hypotheses for the primary endpoint are stated in terms of the hazard ratio, HR= λPIM / 
λPBO, where λPIM and λPBO denote the hazard rates of relapse for the pimavanserin treatment 
group and the placebo treatment group, respectively. 
 The null hypothesis for the primary efficacy endpoint is: HR = 1 
 The alternative hypothesis for the primary efficacy endpoint is: HR ≠ 1 
 
The hypotheses for the key secondary endpoint are stated in terms of the hazard ratio, HR= 
λPIM / λPBO, where λPIM and λPBO denote the hazard rates of discontinuation from the double-
blind period for any reason (other than termination of the study by the Sponsor) for the 
pimavanserin treatment group and the placebo treatment group, respectively. 
 The null hypothesis for the key secondary efficacy endpoint is: HR = 1 
 The alternative hypothesis for the key secondary efficacy endpoint is: HR ≠ 1 
9.3 
Sample Size Determination 
This study will enroll approximately 356 subjects in order to randomize approximately 
178 subjects with dementia-related psychosis who meet response criteria (Section 3.3). 
The sample size calculation was based on the following assumptions: a placebo relapse event 
rate of 60% over 26 weeks; a pimavanserin relapse event rate of 35% over 26 weeks (hazard 
ratio = 0.47); a dropout rate of 25% over 26 weeks; an overall two-sided alpha level of 0.05; 
use of a one-sided (0.025) O’Brien-Fleming stopping boundary to adjust for a single interim 
analysis that will be performed when one half of the total planned number of post-
randomization relapse events have occurred; and a power of 90%. The total number of post-
randomization relapse events required at the final analysis is 75 and the calculated sample 
size is 89 in each of the two treatment groups (giving a total estimate of 178 subjects). 
Study enrollment will be closed when approximately 178 subjects have been randomized in 
the double-blind period or when 75 adjudicated post-randomization relapse events have 
occurred. In the event that the randomization rate is lower than anticipated and/or the relapse 
event rate is lower than anticipated, the number enrolled and randomized may be increased 
up to a maximum of 400 randomized subjects in order to observe 75 post-randomization 
relapse events. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 65 of 100 
An interim efficacy analysis will be performed (Section 9.5.8), and the study may be 
terminated early if the interim analysis results meet prespecified stopping criteria. 
9.4 
Subject Populations for Analysis 
The open-label safety analysis set includes all subjects who received at least one dose of 
open-label study drug (pimavanserin). Subjects will be analyzed based on the treatment that 
they actually received. The open-label safety analysis set will be used for analyses of the 
open-label data. 
The double-blind safety analysis set includes all subjects who received at least one dose of 
double-blind study drug (pimavanserin or placebo). Subjects will be analyzed based on the 
treatment that they actually received. The double-blind safety analysis set will be used for all 
analyses of the double-blind safety data. 
The primary efficacy analysis will be based on the Intent-to-treat (ITT) population, defined as 
all randomized subjects. Subjects will be analyzed based on their randomized treatment. The 
ITT population will be used for the double-blind analysis of all efficacy endpoints. 
The per-protocol (PP) analysis set will be defined prior to unblinding the study for the final 
analysis. Subjects will be analyzed based on their randomized treatment. The PP analysis set 
will be used for sensitivity analyses of selected efficacy endpoints.  
The PK analysis set includes all subjects in the safety analysis set who have sufficient 
PK data. 
9.5 
Description of Statistical Methods 
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean, standard deviation, minimum, maximum, and 
median. For categorical variables, summaries will include the number and percentage of 
subjects in each category, using the number of subjects with non-missing values as the 
denominator for the percentages (unless otherwise specified). 
Unless otherwise specified, all reported p-values will be two-sided. All analyses will be 
performed using SAS® V9.4 (SAS Institute, Inc., Cary, North Carolina) or higher. Validation 
and quality control of the tables, listings, and figures containing the results of the statistical 
analyses will follow appropriate standard operating procedures. 
9.5.1 
Primary Efficacy Analyses 
The time from randomization to relapse in the double-blind period will be compared between 
treatment groups using a Cox regression model with effects for treatment group, dementia 
subtype, and region. The nominal p-value, hazard ratio, and 95% confidence interval will be 
reported. Subjects who discontinue early or complete the study without having experienced a 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 66 of 100 
relapse event will be censored at the time of last assessment for relapse. The primary analysis 
will be based on adjudicated relapse events (Section 9.5.7). 
A sensitivity analysis will be performed based on the Investigator assessment of relapse. 
Additional sensitivity analyses to assess the potential impact of informative censoring will be 
specified in the Statistical Analysis Plan. 
Kaplan-Meier curves of time from randomization to relapse will be presented for each 
treatment group. In addition, Kaplan-Meier estimates of the proportion of subjects who 
relapse along with pointwise 95% confidence intervals will be provided for the 26-week 
double-blind period. 
9.5.2 
Key Secondary Analyses 
The key secondary endpoint of time from randomization to discontinuation from the double-
blind period for any reason (other than termination of the study by the Sponsor) will be 
analyzed using the same Cox regression model described above for the primary endpoint 
along with the Kaplan-Meier estimates. 
9.5.3 
Exploratory Efficacy Analyses  
All exploratory efficacy endpoints will be summarized by treatment group using descriptive 
statistics. For all exploratory SAPS endpoints, CGI-S, ZBI, KSS, and EQ-5D-5L, the change 
from double-blind Baseline will be analyzed using mixed model repeated measures 
(MMRM). The independent variables in the model will include the following: treatment 
group (pimavanserin or placebo), visit, treatment by visit interaction, double-blind Baseline 
score, double-blind Baseline score by visit interaction, designated dementia subtype, and 
region. 
CGI-I will be analyzed using an MMRM model with the following independent variables: 
treatment group (pimavanserin or placebo), visit, treatment by visit interaction, double-blind 
Baseline CGI-S score, double-blind Baseline CGI-S score by visit interaction, designated 
dementia subtype, and region. 
The treatment comparisons will be based on the difference in least squares means and will be 
tested at a two-sided alpha level of 0.05. The double-blind Baseline score is defined as the 
last value prior to the first dose of double-blind study drug. 
In addition to the MMRM analyses described above, last observation carried forward (LOCF) 
analyses will also be performed. 
Descriptive summaries of efficacy endpoints, including the number and percent of subjects 
meeting response criteria, will be provided for the open-label period. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 67 of 100 
9.5.4 
Safety Analyses 
All safety results will be summarized using descriptive statistics. Separate summaries will be 
provided for the open-label and double-blind periods. The double-blind summaries will be 
presented by treatment group. Adverse events will be classified into standard terminology 
using MedDRA. Adverse events may also be categorized into categories of special interest. 
Treatment-emergent AEs, TEAEs leading to discontinuation, TEAEs related to study drug, 
TEAEs by maximum severity, serious TEAEs, and serious TEAEs related to study drug will 
all be summarized. Other TEAEs of special interest may also be summarized. 
Descriptive statistics for ECG, vital signs, GCAS, MMSE, ESRS-A total score and all 
subscales, and clinical laboratory parameters, including change from Baseline when 
applicable, will be tabulated by treatment group and timepoint. Additionally, categorical 
analyses will be conducted on the incidence of subjects with prolonged QTc intervals and 
changes in QTc intervals in accordance with ICH guidelines. The incidence of clinically 
significant changes in selected laboratory parameters will also be summarized. 
9.5.5 
Pharmacokinetic Analyses 
Plasma concentration data for pimavanserin and AC-279 will be listed and summarized using 
descriptive statistics. 
If data allow, population PK and PK/PD analyses will be performed to further characterize 
the PK profile and exposure response relationship of pimavanserin using measures of safety 
and efficacy parameters. The results of population PK and PK/PD modeling will be presented 
in a separate report. Investigators, subjects, and Sponsor personnel will remain blinded to 
plasma concentration data from the double-blind period until the unblinding of the clinical 
database at the end of the study. 
9.5.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review safety information 
on a regular basis throughout the study. The DSMB will be independent of the Sponsor 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. 
9.5.7 
Independent Adjudication Committee 
An IAC will be established to perform validation of protocol-defined relapse events. The 
validation is based on review of predefined clinical data related to: 1) a relapse (identified by 
the Investigator) occurring before the study discontinuation date, and 2) all early termination 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 68 of 100 
events which occur in the double-blind period before the study discontinuation date 
(Section 3.1). 
Predefined clinical data consist of copies of source documents collected and delivered by the 
investigational sites. The IAC will review copies in English (translated if necessary) of 
medical documentation received in the adjudication packages. The Investigator must provide 
medical documentation as soon as possible after early termination. 
The IAC is composed of permanent members covering required medical specialties. IAC 
members must disclose any potential conflicts of interest and must be independent of the 
Sponsor. 
The events will be reviewed by the IAC in a blinded manner. 
Only events that have been adjudicated will be used in the primary efficacy analysis 
(Section 9.5.1) and the interim analysis (Section 9.5.8). Furthermore, only adjudicated events 
will be used to guide the decision to close enrollment in the study, which is based on the 
number of relapse events observed (Section 9.3). 
The IAC will work in accordance with written guidelines included in the IAC charter 
describing in details the composition, tasks, responsibilities and work processes of the 
committee. 
9.5.8 
Planned Interim Analyses 
An interim efficacy analysis of the primary efficacy endpoint will be performed after 
38 adjudicated relapse events have occurred. The study may be terminated early if the interim 
analysis results meet prespecified stopping criteria. For example, if there are exactly 38 
relapse events at the interim analysis, the significance level will be 0.0054. If the study is not 
stopped early and the final analysis includes exactly 75 relapse events (including the 38 
events from the interim analysis), the significance level for the final analysis will be 0.0479. 
The actual significance levels to be used at the interim and final analyses will be calculated 
based on the actual number of adjudicated events observed. The interim efficacy analysis will 
be performed by an independent statistician. Investigators, subjects, and Sponsor personnel 
will remain blinded throughout the study. 
9.5.9 
Additional Subgroup Analyses 
Selected analyses will be performed in subgroups defined by dementia subtype: 
 AD or FTD-spectrum disorders 
 VaD 
 PDD or DLB 
Subgroup analyses by region will also be provided. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 69 of 100 
Additional subgroup analyses may be specified in the statistical analysis plan. Subgroup 
analyses will be performed for both the open-label and double-blind periods. 
9.5.10 
Multiple Comparisons/Multiplicity 
Adjustment of the primary efficacy analysis to account for the interim efficacy analysis is 
described in Section 9.5.8. 
A hierarchical testing procedure will be used to control the overall type I error rate for the 
primary and key secondary efficacy endpoints. Hypothesis testing will occur in the following 
sequential order: 
1. Primary endpoint 
2. Key secondary endpoint 
Statistical significance for the key secondary endpoint may only be claimed if the primary 
endpoint is statistically significant. The stopping boundary to be used for the key secondary 
endpoint will be specified in the SAP. 
9.6 
Enrollment, Randomization, and Masking Procedures 
Eligible subjects will be randomized into 1 of 2 treatment groups (pimavanserin or placebo) 
in a 1:1 ratio using an interactive response technology (IRT) system. Randomization will be 
stratified by: 
1. Most likely dementia subtype or most prominent cause of dementia: 
 AD or FTD-spectrum disorders 
 VaD 
 PDD or DLB 
2. Region 
The assignments will be based on a pre-generated permuted-block randomization 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. 
9.6.1 
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, and for the interim efficacy analysis, the treatment codes will be 
released to an independent statistician/programmer to produce unblinded statistical outputs. 
The Sponsor and the Investigators will remain blinded. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 70 of 100 
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 contact the study Medical 
Monitor to discuss the event, but this need not be prior to unblinding the subject. In an 
emergency situation, the subject’s treatment assignment may be obtained by the Investigator 
from the IRT system. Details of the process to be followed are provided in the 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 agencies. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), Regulatory Agencies (including inspectors), and 
the IRB/EC direct access to source documents (such as original medical records). Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
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 
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 electronic data capture 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 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 71 of 100 
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. 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 
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 and use of prohibited medication during the study 
(Section 4.5.1) will not be granted by the Sponsor under any circumstances. If, during the 
course of a subject’s post-enrollment 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 6.3.8). 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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 72 of 100 
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 Agencies, 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 STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 Quality Control and Quality Assurance 
The Sponsor or designee and Regulatory Agency 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 Agency 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. 
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 73 of 100 
The study will be performed in accordance with 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. When a subject lacks capacity to consent, and 
consent is being provided by an LAR, subject assent for participation must be documented. 
The subject’s study partner/caregiver must also provide written consent 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. 
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. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 74 of 100 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
Copies of signed forms must be given to the signatories and original forms must be 
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 study partner/caregiver must also indicate their understanding of the study and 
their role as a study partner/caregiver to the subject during the study. The subject’s study 
partner/caregiver must provide written consent prior to any Screening visit procedures being 
performed indicating their agreement to participate in the study in the study partner/caregiver 
role. 
Consent for pharmacogenomic testing is optional. Subjects (and LAR, if applicable) must 
sign a separate pharmacogenomics consent form prior to blood draws. The pharmacogenomic 
ICF may be signed at any time during the study. 
Copies of signed forms must be given to the signatories and original forms must be 
maintained in the designated location at the site. 
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. 
 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 75 of 100 
15 LITERATURE REFERENCES 
Åkerstedt T, Gillberg M. Subjective and objective sleepiness in the active individual. 
Int J Neurosci. 1990;52(1-2):29-37. 
American Heart Association. Classes of Heart Failure. 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jsp#.WtedUK_Aipp. Accessed 18 April 2018. 
Andreasen N. Scale for the Assessment of Positive Symptoms (SAPS). Iowa City, IA: 
University of Iowa, 1984. 
Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal 
degeneration. Neurology. 2013;80(5):496-503. 
Ballard C, Bannister C, Graham G, Oyebode F, Wilcock G. Associations of psychotic 
symptoms in dementia sufferers. Br J Psychiatry. 1995;167(4):537-540. 
Ballard C, Banister C, Khan Z, et al. Evaluation of the safety, tolerability, and efficacy of 
pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a phase 2, 
randomised, placebo-controlled, double-blind study. Lancet Neurol. 2018;17(3):213-222. 
Brenowitz WD, Keene CD, Hawes SE, et al. Alzheimer’s disease neuropathologic change, 
Lewy body disease, and vascular brain injury in clinic and community-based samples. 
Neurobiol Aging. 2017;53:83-92. 
Campeau L. Grading of angina pectoris. Circulation. 1976;54:522-523. 
Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). 
Schizophr Res. 2005;76(2-3):247-265. 
Chouinard G, Ross-Chouinard A, Gauthier S, Annable L, Mercier P. An extrapyramidal rating 
scale for idiopathic and neuroleptic-induced Parkinsonism and dyskinesia. Collegium 
Internationale Neuro-Psychopharmacologicum (CINP) 14th Congress, Book of Abstracts. 
1984:16. 
Cohen-Mansfield J, Golander H. The measurement of psychosis in dementia: a comparison 
of assessment tools. Alzheimer Dis Assoc Disord. 2011;25(2):101-118. 
Creese B, Ballard C, Aarsland D, Londos E, Sharp S, Jones E. Determining the association of 
the 5HTTLPR polymorphism with delusions and hallucinations in Lewy body dementias. 
Am J Geriatr Psychiatry. 2014;22(6):580-586. 
Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease 
psychosis: a randomised, placebo-controlled phase 3 trial. The Lancet. 2014;383(9916):533-
540. 

Study ACP-103-045
Final Version: 1.0
Clinical Study Protocol Amendment 1
Date: 16 August 2018
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 76 of 100
DeDeyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and 
haloperidol for behavioral symptoms of dementia. Neurology. 1999;53(5):946-955.
DeMichele-Sweet MA, Sweet RA. Genetics of psychosis in Alzheimer disease: a review. 
J Alzheimers Dis. 2010;19(3):761-780.
Devanand DP, Marder K, Michaels KS, et al. A randomized, placebo-controlled dose-
comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer’s 
disease. Am J Psychiatry. 1998;155(11):1512–1520.
Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone 
in Alzheimer’s disease. N Engl J Med 2012;367:1497-507.
Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with 
Parkinson’s disease. Mov Disord. 2007;22(12):1689-1707.
Fischer CE, Qian W, Schweizer TA, et al. Lewy bodies, vascular risk factors, and subcortical 
arteriosclerotic leukoencephalopathy, but not Alzheimer pathology, are associated with 
development of psychosis in Alzheimer's disease. J Alzheimers Dis. 2016;50(1):283-295.
Folstein MF, Folstein SE, McHugh PR. “Mini-Mental state”: A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura M, et al. Development 
of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled 
analysis of six prospective cohort studies. Lancet Neurol. 2014;13(1):59-66.
Guy W. Clinical Global Impressions. In: ECDEU Assessment Manual for 
Psychopharmacology – Revised (DHEW publication number ADM 76-338). Rockville, MD: 
US Department of Health, Education, and Welfare. 1976; 218-222.
Jellinger KA. Cerebral correlates of psychotic syndromes in neurodegenerative diseases. 
J Cell Mol Med. 2012;16(5):995-1012.
Jeste DV, Finkel SI. Psychosis of Alzheimer's disease and related dementias. Diagnostic 
criteria for a distinct syndrome. Am J Geriatr Psychiatry. 2000;8(1):29-34.
Katz IR, Jeste DV, Mintzer JE, et al. Risperidone Study Group. Comparison of risperidone 
and placebo for psychosis and behavioral disturbances associated with dementia: a 
randomized, double-blind trial. J Clin Psychiatry. 1999;60(2):107-115.
Kim J, Schweizer TA, Fischer CE, Munoz DG. The role of cerebrovascular disease on 
cognitive and functional status and psychosis in severe Alzheimer’s disease. J Alzheimer Dis. 
2017;55(1):381–389.

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 77 of 100 
Kind P. The EuroQol instrument: An index of health related quality of life. In: Spiker B, ed. 
Quality of Life and PharmacoEconomics in Clinical Trials. 2nd ed. Philadelphia, PA: 
Lippincott-Raven Publishers; 1996. 
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy 
bodies: third report of the DLB consortium. Neurology. 2005;65(12):1863-1872. 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement. 2011;7(3):263-269. 
Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpiride in human volunteers. Psychopharmacology (Berl). 2004;176(3-4):331-
342. 
Peretti CS, Danion JM, Kauffmann-Muller F, Grangé D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology (Berl). 1997;131(4):329-338. 
Quaranta D, Bizzarro A, Marra C, et al. Psychotic symptoms in Alzheimer's disease and 5-
HTTLPR polymorphism of the serotonin transporter gene: evidence for an association. 
J Alzheimers Dis. 2009;16(1):173-180. 
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the 
behavioural variant of frontotemporal dementia. Brain. 2011;134(9): 2456-2477. 
Respondek G, Roeber S, Kretzschmar H, et al. Accuracy of the National Institute for 
Neurological Disorders and Stroke/Society for Progressive Supranuclear Palsy and 
Neuroprotection and Natural History in Parkinson Plus Syndromes criteria for the diagnosis 
of progressive supranuclear palsy. Mov Disord. 2013;28(4):504-509. 
Sachdev P, Kalaria R, O’Brien J, et al. Diagnostic criteria for vascular cognitive disorders: a 
VASCOG statement. Alzheimer Dis Assoc Disord. 2014;28(3):206-218. 
Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, 
on cognition and mood. Schizophr Res. 2006;85(1-3):222-231. 
Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs 
in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525-1538. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 78 of 100 
Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral 
symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, 
randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry. 
2000;57(10):968-976. 
Sweet RA, Pollock BG, Sukonick DL, et al. The 5-HTTPR polymorphism confers liability to 
a combined phenotype of psychotic and aggressive behavior in Alzheimer disease. Int 
Psychogeriatr. 2001;13(4):401-409. 
Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation 
of new treatments. Part 1: ethical and scientific issues. Ann Intern Med. 2000; 133(6):455- 
463. 
US Food and Drug Administration. Enrichment strategies for clinical trials to support 
approval of human drugs and biological products. Washington, DC: US Dept of Health and 
Human Services. 2012a. 
US Food and Drug Administration. Safety reporting requirements for INDs and BA/BE 
studies. Washington, DC: US Dept of Health and Human Services. 2012b. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-
918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 
Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: Correlates of 
feelings of burden. Gerontologist. 1980;20(6):649-655. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 79 of 100 
16 APPENDICES 
Appendix A NIA-AA Guidelines for All-cause Dementia and Alzheimer’s Disease 
All-cause Dementia 
Dementia is diagnosed when there are cognitive or behavioral (neuropsychiatric) symptoms 
that: 
1. Interfere with the ability to function at work or at usual activities; and 
2. Represent a decline from previous levels of functioning and performing; and 
3. Are not explained by delirium or major psychiatric disorder; 
4. Cognitive impairment is detected and diagnosed through a combination of (1) history-
taking from the patient and a knowledgeable informant and (2) an objective cognitive 
assessment, either a “bedside” mental status examination or neuropsychological 
testing. Neuropsychological testing should be performed when the routine history and 
bedside mental status examination cannot provide a confident diagnosis. 
5. The cognitive or behavioral impairment involves a minimum of two of the following 
domains: 
a. Impaired ability to acquire and remember new information––symptoms 
include: repetitive questions or conversations, misplacing personal belongings, 
forgetting events or appointments, getting lost on a familiar route. 
b. Impaired reasoning and handling of complex tasks, poor judgment––symptoms 
include: poor understanding of safety risks, inability to manage finances, poor 
decision-making ability, inability to plan complex or sequential activities. 
c. Impaired visuospatial abilities––symptoms include: inability to recognize faces 
or common objects or to find objects in direct view despite good acuity, 
inability to operate simple implements, or orient clothing to the body. 
d. Impaired language functions (speaking, reading, writing)––symptoms include: 
difficulty thinking of common words while speaking, hesitations; speech, 
spelling, and writing errors. 
e. Changes in personality, behavior, or comportment––symptoms include: 
uncharacteristic mood fluctuations such as agitation, impaired motivation, 
initiative, apathy, loss of drive, social withdrawal, decreased interest in 
previous activities, loss of empathy, compulsive or obsessive behaviors, 
socially unacceptable behaviors 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 80 of 100 
Probable Alzheimer’s Disease Dementia 
Meets criteria for all-cause dementia (see above) and in addition, has the following 
characteristics: 
1. Insidious onset. Symptoms have a gradual onset over months to years, not sudden over 
hours or days; 
2. Clear-cut history of worsening of cognition by report or observation; and 
3. The initial and most prominent cognitive deficits are evident on history and 
examination in one of the following categories: 
a. Amnestic presentation: It is the most common syndromic presentation of AD 
dementia. The deficits should include impairment in learning and recall of 
recently learned information. There should also be evidence of cognitive 
dysfunction in at least one other cognitive domain, as defined earlier in the 
text. 
b. Nonamnestic presentations: 
i. Language presentation: The most prominent deficits are in word-
finding, but deficits in other cognitive domains should be present. 
ii. Visuospatial presentation: The most prominent deficits are in spatial 
cognition, including object agnosia, impaired face recognition, 
simultanagnosia, and alexia. Deficits in other cognitive domains should 
be present. 
iii. Executive dysfunction: The most prominent deficits are impaired 
reasoning, judgment, and problem solving. Deficits in other cognitive 
domains should be present. 
4. The diagnosis of probable AD dementia should not be applied when there is evidence 
of  
a. substantial concomitant cerebrovascular disease, defined by a history of a 
stroke temporally related to the onset or worsening of cognitive impairment; or 
the presence of multiple or extensive infarcts or severe white matter 
hyperintensity burden; or 
b. core features of dementia with Lewy bodies other than dementia itself; or 
c. prominent features of behavioral variant frontotemporal dementia; or 
d. prominent features of semantic variant primary progressive aphasia or 
nonfluent/agrammatic variant primary progressive aphasia; or  
e. evidence for another concurrent, active neurological disease, or a non-
neurological medical comorbidity or use of medication that could have a 
substantial effect on cognition. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 81 of 100 
Possible Alzheimer’s Disease Dementia 
A diagnosis of possible AD dementia should be made in either of the circumstances 
mentioned in the following paragraphs. 
Atypical course 
Atypical course meets the core clinical criteria in terms of the nature of the cognitive deficits 
for AD dementia, but either has a sudden onset of cognitive impairment or demonstrates 
insufficient historical detail or objective cognitive documentation of progressive decline, 
OR 
Etiologically mixed presentation 
Etiologically mixed presentation meets all core clinical criteria for AD dementia but has 
evidence of (a) concomitant cerebrovascular disease, defined by a history of stroke temporally 
related to the onset or worsening of cognitive impairment; or the presence of multiple or 
extensive infarcts or severe white matter hyperintensity burden; or (b) features of dementia 
with Lewy bodies other than the dementia itself; or (c) evidence for another neurological 
disease or a non-neurological medical comorbidity or medication use that could have a 
substantial effect on cognition. 
Source: McKhann et al. 2011 
Abbreviations: AD=Alzheimer’s disease; NIA-AA=National Institute on Aging-Alzheimer’s Association 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 82 of 100 
Appendix B Movement Disorder Society’s Task Force Clinical Diagnostic Criteria for 
Dementia Associated with Parkinson’s Disease 
I. 
Core features 
a. Diagnosis of Parkinson’s disease according to Queen Square Brain Bank 
criteria 
b. A dementia syndrome with insidious onset and slow progression, 
developing within the context of established Parkinson’s disease and 
diagnosed by history, clinical, and mental examination, defined as: 
o Impairment in more than one cognitive domain 
o Representing a decline from premorbid level 
o Deficits severe enough to impair daily life (social, occupational, or 
personal care), independent of the impairment ascribable to motor or 
autonomic symptoms 
II. 
Associated Clinical features 
a. Cognitive features: 
o Attention: Impaired. Impairment in spontaneous and focused attention, 
poor performance in attentional tasks; performance may fluctuate during 
the day and from day to day 
o Executive functions: Impaired. Impairment in tasks requiring initiation, 
planning, concept formation, rule finding, set shifting or set 
maintenance; impaired mental speed (bradyphrenia) 
o Visuo-spatial functions: Impaired. Impairment in tasks requiring visual-
spatial orientation, perception, or construction 
o Memory: Impaired. Impairment in free recall of recent events or in tasks 
requiring learning new material, memory usually improves with cueing, 
recognition is usually better than free recall 
o Language: Core functions largely preserved. Word finding difficulties 
and impaired comprehension of complex sentences may be present 
b. Behavioral features: 
o Apathy: decreased spontaneity; loss of motivation, interest, and effortful 
behavior 
o Changes in personality and mood including depressive features and 
anxiety 
o Hallucinations: mostly visual, usually complex, formed visions of 
people, animals or objects 
o Delusions: usually paranoid, such as infidelity, or phantom boarder 
(unwelcome guests living in the home) delusions 
o Excessive daytime sleepiness 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 83 of 100 
III. 
Features which do not exclude PDD, but make the diagnosis uncertain 
 Coexistence of any other abnormality which may by itself cause cognitive 
impairment, but judged not to be the cause of dementia (e.g., presence of 
relevant vascular disease in imaging) 
 Time interval between the development of motor and cognitive symptoms not 
known 
IV. 
Features suggesting other conditions or diseases as cause of mental 
impairment, which, when present make it impossible to reliably diagnose 
PDD: 
 Cognitive and behavioral symptoms appearing solely in the context of other 
conditions such as: 
o Acute confusion due to 
a. Systemic diseases or abnormalities 
b. Drug intoxication 
o Major Depression according to DSM IV 
 Features compatible with “Probable Vascular dementia” criteria according to 
NINDS-AIREN (dementia in the context of cerebrovascular disease as 
indicated by focal signs in neurological exam such as hemiparesis, sensory 
deficits, and evidence of relevant cerebrovascular disease by brain imaging 
AND a relationship between the two as indicated by the presence of one or 
more of the following: onset of dementia within 3 months after a recognized 
stroke, abrupt deterioration in cognitive functions, and fluctuating, stepwise 
progression of cognitive deficits) 
Source: Emre et al. 2007 
Abbreviations: DSM=Diagnostic and Statistical Manual of Mental Disorders; NINDS-AIREN=National 
Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et 
l’Enseignement en Neurosciences; PDD=Parkinson’s disease dementia 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 84 of 100 
Appendix C Dementia with Lewy Bodies Consortium Clinical Diagnostic Criteria 
1. Central feature (essential for a diagnosis of possible or probable DLB) 
a. Dementia defined as progressive cognitive decline of sufficient magnitude 
to interfere with normal social or occupational function. 
b. Prominent or persistent memory impairment may not necessarily occur in 
the early stages but is usually evident with progression. 
c. Deficits on tests of attention, executive function, and visuospatial ability 
may be especially prominent. 
2. Core features (two core features are sufficient for a diagnosis of probable DLB, 
one for possible DLB) 
a. Fluctuating cognition with pronounced variations in attention and alertness 
b. Recurrent visual hallucinations that are typically well formed and detailed 
c. Spontaneous features of parkinsonism 
3. Suggestive features (If one or more of these is present in the presence of one or 
more core features, a diagnosis of probable DLB can be made. In the absence of 
any core features, one or more suggestive features is sufficient for possible DLB. 
Probable DLB should not be diagnosed on the basis of suggestive features alone.) 
a. REM sleep behavior disorder 
b. Severe neuroleptic sensitivity 
c. Low dopamine transporter uptake in basal ganglia demonstrated by SPECT 
or PET imaging 
4. Supportive features (commonly present but not proven to have diagnostic 
specificity) 
a. Repeated falls and syncope 
b. Transient, unexplained loss of consciousness 
c. Severe autonomic dysfunction (e.g., orthostatic hypotension, urinary 
incontinence) 
d. Hallucinations in other modalities 
e. Systematized delusions 
f. Depression 
g. Relative preservation of medial temporal lobe structures on CT/MRI scan 
h. Generalized low uptake on SPECT/PET perfusion scan with reduced 
occipital activity 
i. Abnormal (low uptake) MIBG myocardial scintigraphy 
j. Prominent slow wave activity on EEG with temporal lobe transient sharp 
waves 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 85 of 100 
5. A diagnosis of DLB is less likely 
a. In the presence of cerebrovascular disease evident as focal neurologic signs 
or on brain imaging 
b. In the presence of any other physical illness or brain disorder sufficient to 
account in part or in total for the clinical picture 
c. If parkinsonism only appears for the first time at a stage of severe dementia 
6. Temporal sequence of symptoms 
 DLB should be diagnosed when dementia occurs before or concurrently 
with parkinsonism (if it is present). The term Parkinson disease dementia 
(PDD) should be used to describe dementia that occurs in the context of 
well-established Parkinson disease. In a practice setting the term that is most 
appropriate to the clinical situation should be used and generic terms such as 
LB disease are often helpful. In research studies in which distinction needs 
to be made between DLB and PDD, the existing 1-year rule between the 
onset of dementia and parkinsonism DLB continues to be recommended. 
Adoption of other time periods will simply confound data pooling or 
comparison between studies. In other research settings that may include 
clinicopathologic studies and clinical trials, both clinical phenotypes may be 
considered collectively under categories such as LB disease or alpha-
synucleinopathy. 
Source: McKeith et al. 2005 
Abbreviations: CT=computed tomography; DLB=dementia with Lewy bodies; EEG=electroencephalography; 
LB=Lewy body; MIBG=metaiodobenzylguanidine; MRI=magnetic resonance imaging; PDD=Parkinson’s 
disease dementia; PET=positron emission tomography; SPECT=single photon emission computed 
tomography 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 86 of 100 
Appendix D International Consensus Criteria for Behavioral Variant Frontotemporal 
Dementia 
I. 
Neurodegenerative disease 
The following symptom must be present to meet criteria for bvFTD 
A. Shows progressive deterioration of behavior and/or cognition by observation or 
history (as provided by a knowledgeable informant) 
II. 
Possible bvFTD 
Three of the following behavioral/cognitive symptoms (A-F) must be present to meet 
criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single 
or rare events. 
A. Early* behavioral disinhibition [one of the following symptoms (A.1-A.3) must 
be present]: 
A.1. 
Socially inappropriate behavior 
A.2. 
Loss of manners or decorum 
A.3. 
Impulsive, rash or careless actions 
B. Early apathy or inertia [one of the following symptoms (B.1-B.2) must be 
present]: 
B.1. 
Apathy 
B.2. 
Inertia 
C. Early loss of sympathy or empathy [one of the following symptoms (C.1-C.2) 
must be present]: 
C.1. 
Diminished response to other people’s needs and feelings 
C.2. 
Diminished social interest, interrelatedness or personal warmth 
D. Early perseverative, stereotyped or compulsive/ritualistic behavior [one of the 
following symptoms (D.1–D.3) must be present]: 
D.1. 
Simple repetitive movements 
D.2. 
Complex, compulsive or ritualistic behaviors 
D.3. 
Stereotypy of speech 
E. Hyperorality and dietary changes [one of the following symptoms (E.1-E.3) 
must be present]: 
E.1. 
Altered food preferences 
E.2. 
Binge eating, increased consumption of alcohol or cigarettes 
E.3. 
Oral exploration or consumption of inedible objects 
F. Neuropsychological profile: executive/generation deficits with relative sparing 
of memory and visuospatial functions [all of the following symptoms (F.1-F.3) 
must be present]: 
F.1. 
Deficits in executive tasks 
F.2. 
Relative sparing of episodic memory 
F.3. 
Relative sparing of visuospatial skills 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 87 of 100 
III. 
Probable bvFTD 
All of the following symptoms (A-C) must be present to meet criteria. 
A. Meets criteria for possible bvFTD 
B. Exhibits significant functional decline (by caregiver report or as evidenced by 
Clinical Dementia Rating Scale or Functional Activities Questionnaire scores) 
C. Imaging results consistent with bvFTD [one of the following (C.1-C.2) must be 
present]: 
C.1. 
Frontal and/or anterior temporal atrophy on MRI or CT 
C.2. 
Frontal and/or anterior temporal hypoperfusion or hypometabolism 
on PET or SPECT 
IV. 
Behavioral variant FTD with definite FTLD Pathology 
Criterion A and either criterion B or C must be present to meet criteria. 
A. Meets criteria for possible or probable bvFTD 
B. Histopathological evidence of FTLD on biopsy or at post-mortem 
C. Presence of a known pathogenic mutation 
V. 
Exclusionary criteria for bvFTD 
Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be 
positive for possible bvFTD but must be negative for probable bvFTD. 
A. Pattern of deficits is better accounted for by other non-degenerative nervous 
system or medical disorders 
B. Behavioral disturbance is better accounted for by a psychiatric diagnosis 
C. Biomarkers strongly indicative of Alzheimer’s disease or other 
neurodegenerative process 
Source: Rascovsky et al. 2011 
Abbreviations: bvFTD=behavioral variant frontotemporal dementia; CT=computed tomography; 
FTLD=frontotemporal lobar degeneration; MRI=magnetic resonance imaging; PET=positron emissions 
tomography; SPECT=single photon emission computed tomography 
*As a general guideline “early” refers to symptom presentation within the first 3 years 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 88 of 100 
Appendix E Neuroprotection and Natural History in Parkinson Plus Syndromes 
Diagnostic Criteria for Progressive Supranuclear Palsy 
Inclusion Criteria 
Exclusion Criteria 
All of the following: 
 Supranuclear ophthalmoplegia 
 Postural instability or falls (within 
3 years from disease onset) 
 Akinetic-rigid syndrome 
 Disease duration (12 months to 8 
years) 
 Age at disease onset ≥30 years 
Any of the following: 
 Idiopathic Parkinson’s disease 
 Evidence of any other neurological 
disease that could explain signs 
 History of repeated strokes with 
stepwise progression of parkinsonian 
features 
 History of major stroke 
 Any history of severe or repeated 
head injury 
 History of encephalitis 
 History of neuroleptic use for a 
prolonged period of time or within the 
past 6 months 
 Street-drug–related parkinsonism 
 Significant other neurological disease 
on CT scan/MRI 
 Oculogyric crises 
 Signs of corticobasal degeneration 
 Signs of Lewy body disease 
 Cerebellar ataxia 
 Symptomatic autonomic dysfunction 
 Tremor at rest 
Source: Respondek et al. 2013 
Abbreviations: CT=computed tomography; MRI=magnetic resonance imaging 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 89 of 100 
Appendix F Corticobasal Degeneration Diagnostic Criteria 
Clinical Criteria for Possible Corticobasal Degeneration 
Presentation: 
Insidious onset and gradual progression 
Minimum duration of 
symptoms: 
1 year 
Age at onset: 
No minimum 
Family history (2 or more 
relatives): 
Permitted 
Genetic mutation affecting 
tau (e.g., MAPT): 
Permitted 
Permitted phenotypes: 
Possible 
CBS:  
May be symmetric: 1 of: a) limb rigidity or akinesia, b) limb 
dystonia, c) limb myoclonus plus 1 of: d) orobuccal or limb 
apraxia, e) cortical sensory deficit, f) alien limb phenomena 
(more than simple levitation) 
FBS: 
Two of: a) executive dysfunction, b) behavioral or personality 
changes, c) visuospatial deficits 
NAV: 
Effortful, agrammatic speech plus at least one of: a) impaired 
grammar/sentence comprehension with relatively preserved 
single word comprehension, or b) groping, distorted speech 
production (apraxia of speech) 
PSPS: 
(PLUS ≥1 
CBS feature 
b-f) 
Three of: a) axial or symmetric limb rigidity or akinesia, b) 
postural instability or falls, c) urinary incontinence, d) 
behavioral changes, e) supranuclear vertical gaze palsy or 
decreased velocity of vertical saccades 
Exclusion Criteria: 
1 
Evidence of Lewy body disease: classic 4-Hz Parkinson disease resting 
tremor, excellent and sustained levodopa response, or hallucinations 
2) Evidence of multiple system atrophy: dysautonomia or prominent 
cerebellar signs 
3) Evidence of amyotrophic lateral sclerosis: presence of both upper and 
lower motor neuron signs 
4) Semantic- or logopenic-variant primary progressive aphasia 
5 
Structural lesion suggestive of focal cause. 
6) Granulin mutation or reduced plasma progranulin levels; TDP-43 
mutations; FUS mutations. 
7) Evidence of Alzheimer disease 
Source: Armstrong et al. 2013 
Abbreviations: CBS=corticobasal syndrome; FBS=frontal behavioral-spatial syndrome; 
NAV=Nonfluent/agrammatic variant of primary progressive aphasia; PSPS=progressive supranuclear palsy 
syndrome 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 90 of 100 
Appendix G VASCOG Criteria for Vascular Dementia 
A. One of the following clinical features: 
1. The onset of the cognitive deficits is temporally related to one or more 
cerebrovascular events (CVE). [Onset is often abrupt with a stepwise or fluctuating 
course owing to multiple such events, with cognitive deficits persisting beyond three 
months after the event. However, subcortical ischemic pathology may produce a 
picture of gradual onset and slowly progressive course, in which case A2 applies]. 
The evidence of CVEs is one of the following: 
a. Documented history of a stroke, with cognitive decline temporally associated 
with the event 
b. Physical signs consistent with stroke (e.g., hemiparesis, lower facial 
weakness, Babinski sign, sensory deficit including visual field defect, 
pseudobulbar syndrome – supranuclear weakness of muscles of face, tongue 
and pharynx, spastic dysarthria, swallowing difficulties and emotional 
incontinence) 
2. Evidence for decline is prominent in speed of information processing, complex 
attention and/or frontal-executive functioning in the absence of history of a stroke or 
transient ischemic attack. One of the following features is additionally present: 
a. Early presence of a gait disturbance (small step gait or marche petits pas, or 
magnetic, apraxic-ataxic or parkinsonian gait); This may also manifest as 
unsteadiness and frequent, unprovoked falls 
b. Early urinary frequency, urgency, and other urinary symptoms not explained 
by urologic disease 
c. Personality and mood changes: abulia, depression, or emotional incontinence 
B. Presence of significant neuroimaging (MRI or CT) evidence of cerebrovascular disease 
(one of the following): 
1. One large vessel infarct is sufficient for Mild VCD, and two or more large vessel 
infarcts are generally necessary for VaD (or Major VCD). 
2. An extensive or strategically placed single infarct, typically in the thalamus or basal 
ganglia may be sufficient for VaD (or Major VCD). 
3. Multiple lacunar infarcts (> two) outside the brainstem; 1–2 lacunes may be 
sufficient if strategically placed or in combination with extensive white matter 
lesions. 
4. Extensive and confluent white matter lesions 
5. Strategically placed intracerebral hemorrhage, or two or more intracerebral 
hemorrhages 
6. Combination of the above 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 91 of 100 
Exclusion criteria (for Mild and Major VCD) 
1. History 
a. Early onset of memory deficit and progressive worsening of memory and 
other cognitive functions such as language (transcortical sensory aphasia), 
motor skills (apraxia), and perception (agnosia), in the absence of 
corresponding focal lesions on brain imaging or history of vascular events. 
b. Early and prominent parkinsonian features suggestive of Lewy body disease 
c. History strongly suggestive of another primary neurological disorder such as 
multiple sclerosis, encephalitis, toxic or metabolic disorder, etc. sufficient to 
explain the cognitive impairment. 
2. Neuroimaging 
a. Absent or minimal cerebrovascular lesions on CT or MRI 
3. Other medical disorders severe enough to account for memory and related symptoms 
a. Other disease of sufficient severity to cause cognitive impairment (e.g., brain 
tumor, multiple sclerosis, encephalitis) 
b. Major depression, with a temporal association between cognitive impairment 
and the likely onset of depression. 
c. Toxic and metabolic abnormalities, all of which may require specific 
investigations 
4. Other medical disorders severe enough to account for memory and related symptoms 
a. Other disease of sufficient severity to cause cognitive impairment (e.g., brain 
tumor, multiple sclerosis, encephalitis) 
b. Major depression, with a temporal association between cognitive impairment 
and the likely onset of depression. 
c. Toxic and metabolic abnormalities, all of which may require specific 
investigations 
Source: Sachdev et al. 2014 
Abbreviations: CT=computed tomography; CVE=cerebrovascular events; MRI=magnetic resonance imaging; 
VaD=vascular dementia; VASCOG=International Society for Vascular Behavioral and Cognitive Disorders; 
VCD=vascular cognitive disorder 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 92 of 100 
Appendix H Prohibited and Restricted Medications 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. 
A restricted medication is allowed only under certain conditions. Details regarding 
procedures for subjects who take a prohibited medication during the study are provided in 
Section 4.5.1. 
Medication Class 
Medication1 
Prohibition/restrictions 
Antipsychotics other 
than pimavanserin 
PROHIBITED 
All in class 
 
Must be washed out 2 weeks or 5 half-lives 
(whichever is longer) prior to open-label Baseline 
 
Prohibited throughout the study 
Anticholinergics 
PROHIBITED 
 
Centrally acting 
anticholinergics 
o 
benztropine 
o 
biperiden 
o 
trihexiphenidyl 
o 
Oral 
diphenhydramine 
 
Anticholinergic medications whose primary 
mechanism of action is centrally acting are 
prohibited and should be washed out and 
discontinued at least 2 weeks or 5 half-lives 
(whichever is longer) prior to open-label Baseline 
UNRESTRICTED 
 
Peripherally acting 
anticholinergics 
 
Topical 
diphenhydramine 
 
Peripherally acting anticholinergic medications 
and topical diphenhydramine are allowed without 
restriction 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
 
carbamazepine 
 
lamotrigine 
 
lithium 
 
phenytoin 
 
Must be washed out 5 half-lives prior to Baseline 
 
Prohibited throughout the study 
RESTRICTED 
 
valproate 
 
Valproate may be used if dose unchanged for at 
least 4 weeks prior to Baseline and dose should 
be expected to remain unchanged until the 
subject’s final visit. 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 93 of 100 
Medication Class 
Medication1 
Prohibition/restrictions 
Antidepressants 
PROHIBITED 
 
mirtazapine 
 
nefazadone 
 
fluvoxamine 
 
mianserin 
 
trazodone 
 
amitriptyline 
 
nortriptyline 
 
imipramine 
 
trimipramine 
 
desipramine 
 
clomipramine 
 
Prohibited throughout the study 
 
Must be discontinued at least 2 weeks or 5 half-
lives (whichever is longer) prior to the Baseline 
visit 
RESTRICTED 
 
citalopram 
 
escitalopram 
 
venlafaxine 
 
If subject is remaining on these medications, the 
dose of the permitted antidepressants on the left 
must be unchanged for at least 4 weeks prior to 
Baseline and should be expected to remain 
unchanged until the subject’s final visit. If the 
medication is being discontinued, it must be 
discontinued at least 2 weeks or 5 half-lives 
(whichever is longer) prior to the Baseline visit. 
o 
Citalopram is restricted to a 
maximum dose of 20 mg/day  
o 
Escitalopram is restricted to a 
maximum dose of 10 mg/day  
o 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day 
Anxiolytics 
PROHIBITED 
 
chlordiazepoxide 
 
diazepam 
 
flurazepam 
 
Prohibited at study entry and throughout the study 
RESTRICTED 
 
alprazolam 
 
clonazepam 
 
lorazepam 
 
oxazepam 
 
temazepam 
 
midazolam 
 
triazolam 
 
Short- or medium-acting benzodiazepine may be 
used for acute anxiety. Reasonable efforts should 
be made to use minimum dose necessary for 
symptom management. 
 
May not be used within 12 hours prior to an 
assessment visit 
Hypnotics and 
sleeping agents 
PROHIBITED 
 
zolpidem 
 
zopiclone 
 
eszopiclone 
 
Prohibited at study entry and throughout the study

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 94 of 100 
Medication Class 
Medication1 
Prohibition/restrictions 
RESTRICTED 
 
zaleplon 
 
ramelteon 
 
May not be used within 12 hours of a cognitive 
assessment, and efforts should be made to limit 
agents to lowest dose for the shortest time 
needed. 
Stimulants and wake-
promoting agents 
PROHIBITED 
 
methylphenidate 
 
modafinil 
 
armodafinil 
 
Prohibited at study entry and throughout the study 
(see Section 6.3.7 for procedures related to a 
positive amphetamine test at study entry) 
Non-stimulant 
ADHD medications 
PROHIBITED 
 
atomoxetine 
 
Prohibited at study entry and throughout the study 
Serotonin antagonists  PROHIBITED 
 
cyproheptadine 
 
Prohibited throughout the study 
 
Must be discontinued at least 3 weeks prior to the 
Baseline visit 
Antiarrhythmic drugs 
PROHIBITED 
 
ajmaline 
 
amakalant, semantilide 
 
amiodarone 
 
bretylium 
 
disopyramide 
 
dofetilide 
 
dronedarone 
 
flecainide 
 
ibutilide 
 
procainamide 
 
propafenone 
 
quinidine 
 
sotalol, d-sotalol 
 
Prohibited at study entry and throughout the study 
Opioids 
PROHIBITED 
 
methadone 
 
Prohibited at study entry and throughout the study 

Study ACP-103-045
Final Version: 1.0
Clinical Study Protocol Amendment 1
Date: 16 August 2018
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 95 of 100
Medication Class
Medication1
Prohibition/restrictions
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 

clarithromycin

erythromycin

levofloxacin

moxifloxacin

pentamidine

roxithromycin

Prohibited at study entry and throughout the study
RESTRICTED 

artenimol/piperaquine

azithromycin

bedaquiline

ciprofloxacin

gemifloxacin

norfloxacin

ofloxacin

fluconazole

telavancin

telithromycin

Prohibited at Baseline but may be used during the
course of the study to treat a bacterial infection
(e.g., urinary tract infection, respiratory
infection), post-Baseline at the discretion of the
Principal Investigator.

The medications on the left are only allowed
under the following conditions:
o
The subject has a Baseline ECG with a QTcF
<425 ms IF QRS duration is <120 ms OR
o
The subject has a QTcF <450 ms at Baseline
IF QRS duration ≥120 ms
1 
Medications within each class include but are not limited to the examples listed in this table.

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 96 of 100 
Appendix I 
Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP 3A4 enzyme (CYP3A4) inhibitors and inducers. Any questions 
should be discussed with the Medical Monitor or appropriate designee. Details regarding 
procedures for subjects who take a prohibited medication during the study are provided in 
Section 4.5.1. 
The metabolism of pimavanserin is affected by strong CYP3A4 inhibitors, resulting in an 
increase in maximum plasma concentration (Cmax) and area under the plasma concentration-
time curve (AUC) of approximately 3-fold. 
Strong inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to 
investigational product administration, whichever is longer. Strong inducers of CYP3A4 are 
to be stopped 30 days or 5 half-lives prior to investigational product administration, 
whichever is longer. 
Moderate inhibitors and inducers of CYP3A4 may be allowed but should be used with 
caution. 
STRONG 
INHIBITORS 
grapefruit juice
a 
boceprevir (Victrelis®) 
clarithromycin (Biaxin®) 
cobicistat (part of Stribild®) 
conivaptan (Vaprisol®) 
fluvoxamine (Luvox®) 
indinavir (Crixivan®) 
itraconazole (Sporanox®) 
ketoconazole (Nizoral®) 
lopinavir and ritonavir (Kaletra®) 
mibefradil (Posicor®) 
nefazodone (Serzone®) 
nelfinavir (Viracept®) 
posaconazole (Noxafil®) 
quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira Pak™) 
saquinavir (Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
grapefruit juice
a 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
erythromycin (Erythrocin® 
Lactobionate) 
fluconazole (Diflucan®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 
verapamil (Calan®) 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 97 of 100 
STRONG 
INDUCERS 
avasimibe 
carbamazepine (Tegretol®) 
phenobarbital (Luminal®, Solfoton®) 
phenytoin (Dilantin®)  
rifampin (Rifadin®, Rifadin® IV, 
Rimactane®) 
St. John's Wort 
MODERATE 
INDUCERS 
bosentan (Tracleer®) 
efavirenz (Sustiva®) 
etravirine (Intelence®) 
modafinil (Provigil®) 
nafcillin (Unipen®, Nallpen®) 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 98 of 100 
Appendix J 
New York Heart Association Classification of Heart Failure 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of 
breath).  
III 
Marked limitation of physical activity. Comfortable at rest. Less 
than ordinary activity causes fatigue, palpitation, or dyspnea.  
IV 
Unable to carry on any physical activity without discomfort. 
Symptoms of heart failure at rest. If any physical activity is 
undertaken, discomfort increases.  
Source: American Heart Association 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 99 of 100 
Appendix K Canadian Cardiovascular Society Angina Grading Scale 
Grade 
Description 
I 
Ordinary physical activity does not cause angina, such as walking 
and climbing stairs. Angina with strenuous or rapid or prolonged 
exertion at work or recreation 
II 
Slight limitation of ordinary activity. Walking or climbing stairs 
rapidly, walking uphill, walking or stair climbing after meals, or 
in cold, or in wind, or under emotional stress, or only during the 
few hours after awakening. Walking more than two blocks on the 
level and climbing more than one flight of ordinary stairs at a 
normal pace and in normal conditions 
III 
Marked limitation of ordinary physical activity. Walking one or 
two blocks on the level and climbing one flight of stairs in normal 
conditions and at normal pace 
IV 
Inability to carry on any physical activity without discomfort, 
anginal syndrome may be present at rest 
Sources: Campeau L 1976 
 
 

Study ACP-103-045 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
Date: 16 August 2018 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. Page 100 of 100 
Appendix L Predictors Composing the PHASES Aneurysm Rupture Risk Score 
PHASES aneurysm risk score 
Points 
(P) Population 
North American, European (other than Finnish) 
0 
Japanese 
3 
Finnish 
5 
(H) Hypertension 
No 
0 
Yes 
1 
(A) Age 
<70 years 
0 
≥70 years 
1 
(S) Size of aneurysm 
<7.0 mm 
0 
7.0-9.9 mm 
3 
10.0-19.9 mm 
6 
≥20 mm 
10 
(E) Earlier SAH from another aneurysm 
No 
0 
Yes 
1 
(S) Site of aneurysm 
ICA 
0 
MCA 
2 
ACA/Pcom/posterior 
4 
Source: Greving et al. 2014 
Abbreviations: ACA=anterior cerebral arteries (including the anterior cerebral artery, anterior communicating 
artery, and pericallosal artery); ICA=internal carotid artery; MCA=middle cerebral artery; Pcom=posterior 
communicating artery; posterior=posterior circulation (including the vertebral artery, basilar artery, 
cerebellar arteries, and posterior cerebral artery); SAH=subarachnoid haemorrhage  
Note: To calculate the PHASES risk score for an individual, the number of points associated with each indicator 
can be added up to obtain the total risk score.