Conditions: Parkinson's Disease Psychosis
Keywords: Parkinson's Disease Psychosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 459
Healthy volunteers: no

Brief summary:
To assess the long-term safety and tolerability of ACP-103 in subjects with Parkinson's disease psychosis.

Detailed description:
This study did not have a fixed duration, and the duration of individual subject participation was determined based on investigator assessment of subject tolerability and continued benefit until such time as either the drug was commercially available in the US, or an alternate treatment extension was available in non-US regions. For this reason, no subjects, therefore, were considered to have "completed" the study.

Arms:
arm 1: Tablets taken once daily by mouth for as long as ACP-103 is considered to be tolerated and beneficial to subjects

Interventions: intervention 1: Pimavanserin tartrate (ACP-103)
Intervention descriptions: intervention 1: Tablets taken once daily by mouth for as long as ACP-103 is considered to be tolerated and beneficial to subjects

Protocol document:
Prot_000.pdf: 
Official Title: A multi-center, open-label extension study to examine the safety and 
tolerability of ACP-103 in the treatment of psychosis in Parkinson’s Disease 
NCT Number: NCT00550238 
Date of IRB Approval: 16 Jul 2010 


 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
 
 
ACADIA Pharmaceuticals Inc. 
 
 
CLINICAL STUDY PROTOCOL 
 
A Multi-Center, Open-Label Extension Study to 
Examine the Safety and Tolerability of ACP-103 in the 
Treatment of Psychosis in  
Parkinson’s Disease 
 
 
 
 
 
 
Protocol Number: ACP-103-015 
 
EUDRACT Number: 2007-003035-22 
 
 
Protocol Amendment No. 6 Date:  June 30, 2010 
Protocol Amendment No. 5 Date: August 4, 2008 
Protocol Amendment No. 4 Date: April 14, 2008 
Protocol Amendment No. 3 Date: November 14, 2007 
Protocol Amendment No. 2 Date: August 30, 2007 
Protocol Amendment No. 1 Date: June 14, 2007 
Final Protocol Date: April 12, 2007 
 
   
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. 


A CADI A Pharmaceuticals 
Protocol Amendment #6 ACP-103-015 
Sponsor Signatory: 
Sponsor Team Lead: 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 2 
June 30, 2010 


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PROTOCOL SYNOPSIS 
Title 
A Multi-Center, Open-Label Extension Study to Examine the Safety 
and Tolerability of Pimavanserin in the Treatment of Psychosis in 
Parkinson’s Disease 
Protocol Number 
ACP-103-015 
Methodology 
This study will be conducted as a multi-center, open-label extension 
study.  Subjects who have completed blinded treatment in a previous 
study of pimavanserin in Parkinson’s disease psychosis, and who may, 
in the opinion of the Investigator, benefit from treatment with 
pimavanserin, will be enrolled in this extension study for safety 
evaluation.  Subjects may be enrolled in ACP-103-015 as early as the 
last visit of the treatment phase of the prior blinded study OR up to 28 
days following completion of this blinded treatment period.  
Subjects who enroll in ACP-103-015 within one week of completion 
of the treatment phase of the prior blinded study will NOT be required 
to complete a full Baseline visit (Day 1).   
Subjects who are enrolled greater than one week following completion 
of the prior blinded study will be required to complete a full baseline 
evaluation for ACP-103-015. 
Once per day, subjects will be administered 40 mg of pimavanserin, 
orally, preferably in the morning.  Dose escalation and reduction will 
NOT be allowed.     
All subjects will be required to visit the study site at Week 2, Month 1, 
Month 3, Month 6, Month 9, Month 12 and every six months 
thereafter to complete safety and clinical evaluations. Unscheduled 
clinical evaluations may occur at anytime if deemed appropriate by the 
Investigator. 
Study Duration  
The duration of this extension study will be determined based on 
clinical grounds, but may continue for as long as pimavanserin is 
considered to be tolerated and beneficial to subjects and until such 
time as pimavanserin is approved and commercially available.  
Study Centers 
This is a multi-center study with approximately 150 sites  
Objectives 
Primary Objective: 
• To assess long-term safety and tolerability of pimavanserin in 
subjects with Parkinson’s Disease Psychosis (PDP)  
Number of 
Subjects 
All subjects that complete the blinded treatment period of a previous 
study of pimavanserin in PDP and meet eligibility criteria may enroll 
in this study.   


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Inclusion/Exclusion 
Criteria 
The study population is defined as subjects who meet the following 
criteria: 
Inclusion Criteria: 
1. Subject has completed the blinded treatment period of a previous
study of pimavanserin in PDP within the last 28 days and, who
may, in the opinion of the Investigator, benefit from therapy with
pimavanserin
2. Subject must have clear sensorium at study entry (i.e., oriented to
time, person, and place) and thus not be delirious
3. Female subjects must be of non-childbearing potential (defined as
either surgically sterilized or at least 1 year post-menopausal) or
must agree to use a clinically acceptable method of contraception
(such as intrauterine device [IUD], diaphragm, or oral, injectable
[e.g. Depo-Provera] or implantable contraception [e.g. Norplant
System]) during the study and one month following completion of
the study
4. The subject is willing and able to provide consent
5. Caregiver is willing and able to provide consent and agrees to
accompany the subject to all visits
Exclusion Criteria: 
1. Subject has current evidence of a clinically significant concurrent
medical illness including: severe cardiac disease (recent
myocardial infarction, congestive heart failure or cardiac syncope),
severe pulmonary disease (chronic obstructive pulmonary disease
or emphysema), renal insufficiency or failure, hepatitis, a recent
diagnosis of malignancy (excluding basal or squamous cell
carcinoma), a serious and or unstable gastrointestinal, hematologic
or other medical disorder
2. Subject is using any of the medications prohibited or restricted as
described in Appendix 1 (Prohibited and Restricted Concomitant
Medications
3. Subject is on medications known to prolong the QT interval (as 
described in Appendix 1)
4. Subject has a baseline electrocardiogram (ECG) with Bazett’s
corrected QT  (QTcB) of greater than 460 msec if male or 470
msec if female
5. Subject had an allergy or sensitivity to pimavanserin based on
known allergies to drugs of the same class
6. Subject is judged by the Investigator to be inappropriate for the
study


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Study Product, 
Dose, Route, 
Regimen 
Pimavanserin will be administered orally, once a day.  Two 20 mg 
tablets will be used to administer a 40 mg dose.  Dose escalation and 
reduction will not be allowed.  
Criteria for 
Evaluation  
Safety: 
• The safety of subjects will be assessed by monitoring adverse 
events, physical examinations, vital signs, clinical laboratory tests 
(hematology, clinical chemistry, and urinalysis), ECGs, and pre-
dose plasma pimavanserin concentrations 
 
Six clinical rating scales will be administered and data will be 
recorded for the following: 
 
• The combined score for the Hallucinations and Delusions domains 
of the Scale for the Assessment of Positive Symptoms (SAPS). 
• Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II and III 
• Clinical Global Impression Scale (CGI) with emphasis on severity 
(CGI-S) and improvement (CGI-I) of psychosis 
• The Caregiver Burden Scale 
• Resource Utilization in Dementia Scale (RUD Lite) 
Statistical Analyses  Safety analyses will be conducted on adverse events, clinical 
laboratory tests, ECGs, physical exams and vital signs. No formal 
analyses will be conducted on the clinical efficacy data. 


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TABLE OF CONTENTS 
SIGNATURES ....................................................................................................................... 2 
PROTOCOL SYNOPSIS ...................................................................................................... 3 
TABLE OF CONTENTS ...................................................................................................... 6 
LIST OF ABBREVIATIONS ............................................................................................... 9 
1.
BACKGROUND INFORMATION .......................................................................... 11
1.1 
INVESTIGATIONAL DRUG .................................................................................... 12 
1.2 
PREVIOUS CLINICAL EXPERIENCE ...................................................................................... 12 
1.3 
RATIONALE FOR THE STUDY ................................................................................................ 13 
2. OBJECTIVES ................................................................................................................. 14
3. STUDY DESIGN ............................................................................................................. 14
3.1 
OVERALL STUDY DESIGN ................................................................................... 14 
3.2 
DOSE RATIONALE ............................................................................................... 14 
3.3 
STUDY DURATION ............................................................................................... 14 
3.4 
NUMBER OF SUBJECTS ........................................................................................ 15 
3.5 
ADMINISTRATION OF PIMAVANSERIN ................................................................. 15 
3.6 
STUDY PROCEDURES ........................................................................................... 15 
3.6.1.Schedule of Events and Assessments .................................................................... 15 
3.6.2.Evaluations by Visit ................................................................................................... 19 
4. SELECTION OF SUBJECTS AND CRITERIA FOR WITHDRAWAL ...................... 21
4.1 
SELECTION OF SUBJECTS ..................................................................................... 21 
4.2 
CRITERIA FOR SUBJECT WITHDRAWAL ............................................................... 22 
5. TREATMENTS ADMINISTERED ............................................................................................... 23
5.1 
IDENTITY OF INVESTIGATIONAL PRODUCTS ........................................................ 23 
5.2 
DOSING ............................................................................................................... 23 
5.3 
CONCOMITANT THERAPY .................................................................................... 23 
5.3.1.Prohibited and Restricted Medications ................................................................. 24 
5.4 
INVESTIGATIONAL DRUG HANDLING .................................................................. 24 
5.4.1.Test Article ................................................................................................ 24 
5.4.2.Drug Packaging ......................................................................................... 24 
5.4.3.Dosage and Administrations ..................................................................... 24 
5.4.4.Receipt of Supplies ................................................................................... 24 
5.4.5.Storage of Investigational Drug ................................................................ 24 
5.4.6.Record of Dispensing ................................................................................ 25 


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5.4.7.Accountability ........................................................................................... 25 
6. ASSESSMENT OF SAFETY ........................................................................................................... 25 
6.1 
PRIMARY OBJECTIVE .......................................................................................... 25 
6.2 
DESCRIPTION OF SAFETY ASSESSMENTS ............................................................. 25 
6.2.1. Updated Medical History ......................................................................... 25 
6.2.2. Physical Examinations and Updated Physical Examinations .................. 26 
6.2.3. Weight .................................................................................................... 26 
6.2.4. Electrocardiogram (ECG) ........................................................................ 26 
6.2.5. Vital Signs ................................................................................................ 27 
6.2.6. Clinical Laboratory Tests ......................................................................... 27 
6.2.7. Adverse Events ........................................................................................ 29 
6.2.8. Overdose of Investigational Medicinal Product....................................... 34 
6.2.9. Pregnancy ................................................................................................. 34 
6.2.10. Emergency Treatment ............................................................................ 34 
7. CLINICAL EVALUATIONS ........................................................................................................... 34 
7.1 
SCALE FOR ASSESSMENT OF POSITIVE SYMPTOMS (SAPS) ................................. 34 
7.2 
UNIFIED PARKINSON’S DISEASE RATING SCALE (UPDRS) ................................ 35 
7.3 
CLINICAL GLOBAL IMPRESSION SCALE (CGI) .................................................... 36 
7.4 
CAREGIVER BURDEN SCALE ............................................................................... 36 
7.5 
RUD LITE ........................................................................................................... 36 
8. ASSESSMENT OF PHARMACOKINETICS .......................................................................... 37 
9. DATA RECORDING, RETENTION, AND MONITORING ............................................. 37 
9.1 
CASE REPORT FORMS ......................................................................................... 37 
9.2 
AVAILABILITY AND RETENTION OF RECORDS ..................................................... 37 
9.3 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................. 38 
9.4 
SUBJECT CONFIDENTIALITY ................................................................................ 38 
10. STATISTICAL PLAN ....................................................................................................................... 39 
10.1 GENERAL STATISTICAL METHODS ...................................................................... 39 
10.2 STUDY SUBJECTS ................................................................................................ 39 
10.2.1. Analysis Population(s) ........................................................................... 39 
10.2.2. Subject Accountability and Subject Disposition .................................... 39 
11. DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................................... 39 
12. SAFETY ANALYSIS ......................................................................................................................... 39 
12.1 ADVERSE EVENTS ............................................................................................... 39 
12.1.1. Clinical Laboratory Values ............................................................................. 39 


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12.1.2. Vital Signs ............................................................................................................ 39 
12.1.3. Electrocardiogram .............................................................................................. 40 
12.1.4. Physical Examinations ...................................................................................... 40 
12.1.5. Pharmacokinetic Analysis ............................................................................... 40 
12.2 EFFICACY ANALYSIS ........................................................................................... 40 
13. REGULATORY COMPLIANCE ................................................................................................ 40 
13.1 ETHICAL CONDUCT OF THE STUDY ..................................................................... 40 
13.2 REGULATORY APPROVAL ................................................................................... 40 
13.3 SUBJECT INFORMED CONSENT ............................................................................ 41 
13.4 SUBJECT COMPENSATION FOR ADVERSE EFFECTS ON HEALTH ........................... 41 
13.5 PROTOCOL AMENDMENTS AND STUDY TERMINATION ........................................ 42 
13.6 FINANCE, INSURANCE AND INDEMNITY .............................................................. 42 
13.7 PUBLICATION ...................................................................................................... 42 
14. DECLARATION OF INVESTIGATOR ................................................................................... 43 
15. REFERENCES ..................................................................................................................................... 44 
16. APPENDICES ................................................................................................................ 46 
APPENDIX 1:  PROHIBITED AND RESTRICTED CONCOMITANT MEDICATIONS ................ 47 
APPENDIX 2: CAREGIVER BURDEN SCALE ..................................................................... 48 
APPENDIX 3: SCALE FOR THE ASSESSMENT OF POSITIVE SYMPTOMS (SAPS) ............... 49 
APPENDIX 4: UNIFIED PARKINSON’S DISEASE RATING SCALE (UPDRS) ...................... 62 
APPENDIX 5: CLINICAL GLOBAL IMPRESSION (CGI) SCALES ........................................ 72 
APPENDIX 6: RESOURCE UTILIZATION IN DEMENTIA (RUD LITE) ................................ 73 
 
LIST OF TABLES 
 
TABLE 1: 
SCHEDULE OF EVENTS AND ASSESSMENTS ............................................................................. 17 
TABLE 2: 
INVESTIGATIONAL PRODUCTS .................................................................................................... 23 


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LIST OF ABBREVIATIONS  
Abbreviation/Acronym Definition 
5HT2A 
serotonin 2A receptor 
5HT2C 
serotonin 2C receptor 
ACADIA 
ACADIA Pharmaceuticals Incorporated, Study Sponsor 
AE(s) 
adverse event(s) 
BP 
blood pressure 
bpm 
beats per minute 
CGI-I 
Clinical Global Impression scale - Improvement 
CGI-S 
Clinical Global Impression scale - Severity 
CRF 
case report form 
D2 
dopamine D2 receptor subtype 
DBP 
diastolic blood pressure 
DO 
Doctor of Osteopathy 
EC 
Ethics Committee 
ECG 
electrocardiogram (or electrocardiograph) 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
MD 
Doctor of Medicine (Latin: Medicinae Doctor) 
mmHg 
millimeters of mercury 
PA 
physician assistant 
PD 
Parkinson’s Disease 
PDP 
Parkinson’s Disease Psychosis 
PK 
Pharmacokinetic 
po 
by mouth (Latin: per os) 
PR 
PR interval on an electrocardiogram tracing 
QRS 
QRS interval of electrocardiogram 
QT 
QT interval of electrocardiogram 
QTcB 
QT interval of electrocardiogram; Bazett’s corrected for heart rate  
ROS 
review of symptoms 


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RR 
respiration rate 
RUD Lite 
Resource Utilization in Dementia Lite 
SAE(s) 
serious adverse event(s) 
SAPS 
Scale for the Assessment of Positive Symptoms 
SBP 
systolic blood pressure 
SOP(s) 
standard operating procedure(s) 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
U.S. 
United States 
 


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1. 
BACKGROUND INFORMATION 
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder; its clinical 
diagnosis is based on the presence of a core set of neurological symptoms including rest tremor, 
bradykinesia, rigidity, and disturbances of balance and posture. Patients also experience a 
number of nonmotor symptoms that are equally important to address. These include psychosis 
and behavioral disturbances, pain, sensory complaints, depression, and dementia (Weintraub and 
Stern, 2005; Aarsland et al., 1999). Among these, perhaps the most significant with respect to 
morbidity and quality of life, and the most difficult to treat, is psychosis. Psychotic symptoms 
occur in 20% to 40% of patients with PD in advanced stages of the disease (Marsh, 2005; 
Fenelon, 2000). Parkinson’s disease psychosis (PDP) manifests primarily as hallucinations and 
delusions; initial symptoms are frequently a sense of presence or passage. 
 
Development of psychosis in a patient with PD is progressive and often devastating as it is 
prognostic of nursing home placement, poses enormous stress on caregivers, and markedly 
increases the risk of mortality in the patient population (Chou and Fernandez, 2006; Factor et al., 
2003). There is no proven safe and effective course of treatment for PDP. Dose reduction of 
dopaminergic treatment is frequently standard practice when psychotic symptoms first present, 
but this practice does not always diminish psychosis and provides only short-term antipsychotic 
benefit. In addition, it usually results in increased motor function deficits.  
 
There are six atypical antipsychotics on the market in the United States (U.S.): aripiprazole, 
clozapine, olanzapine, quetiapine, risperidone, and ziprasidone.  None of these agents are 
approved for the treatment of PDP.  Nevertheless, off-label use of these agents is sometimes 
employed.  The most commonly used for PDP are clozapine and quetiapine. Clozapine is 
effective in PDP and does not cause deterioration of motor function. However, the prescribing 
community is often reluctant to employ clozapine as a first line therapy in the PDP population 
because of (1) the risk of agranulocytosis, (2) the stringent, associated monitoring requirements, 
and (3) other potential idiosyncratic reactions such as myocarditis and cardiomyopathy. 
Quetiapine appears to be the next best option because it minimally affects motor function. In two 
blinded and placebo-controlled trials, quetiapine had no effect on motor function but failed to 
show improvement in psychotic symptoms (Ondo et al., 2005, and Rabey et al., 2006). 
Risperidone and olanzapine have been shown to worsen motoric symptoms in PDP patients and 
are therefore considered inappropriate therapy in this population. More recently, two case studies 
suggest that ziprasidone may be useful in treating PDP, however, the cardiovascular safety 
profile and potential effects on motor function may limit its use. The available data on 
aripiprazole suggest that this agent has variable effects on psychotic symptoms and based on its 
safety profile it should be used with caution in this fragile patient population, because it may 
cause motor worsening. 
 
In addition to the risk of motor effects associated with the other atypical antipsychotics, sedation 
is a serious side effect in this population, which increases risks of falls and fractures. This patient 
population is already at risk given the tendency for frequent somnolence and sleep attacks to 
occur during the day. In addition, a black box warning was recently applied to the label of 
atypical antipsychotics regarding their use in elderly patients with dementia. The Food and Drug 


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Administration (FDA) determined in 2005 that the treatment of behavioral disorders in elderly 
patients with dementia with atypical antipsychotic medications is associated with increased 
mortality. Of a total of 17 placebo-controlled trials performed with olanzapine, aripiprazole, 
risperidone, or quetiapine in elderly demented patients with behavioral disorders, 15 showed 
higher mortality in the drug-treated arm compared with the placebo-treated arm (FDA Public 
Health Advisory issued 11 April 2005). Moreover, a retrospective cohort study, reported that 
typical antipsychotics are as likely as atypical antipsychotics to increase the risk of death in 
elderly patients (Wang et al., 2005), suggesting the dopamine D2 receptor subtype (D2) rather 
than the serotonin 2A receptor (5HT2A) may be involved in the increased mortality. 
 
1.1 
Investigational Drug 
Pimavanserin (pimavanserin tartrate, or ACP-103) is the tartrate salt of the active moiety N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)- N’-(4-(2-
methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1) and is a novel 
small molecule designed to specifically block serotoninergic neurotransmission mediated by the 
5HT2A receptor. At higher doses pimavanserin may block the serotonin 5HT2C receptors. 
 
Although the etiology of PDP is unclear, both scientific and clinical observations support the use 
of a 5HT2A receptor inverse agonist, such as pimavanserin, in this indication (Weiner et al., 
2003). Furthermore, pimavanserin does not bind to dopamine D2 receptors that have been 
implicated in a range of dose-limiting side effects of the existing antipsychotic drugs as well as 
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 PDP and have an 
improved safety profile relative to other antipsychotic agents. 
 
1.2 
Previous Clinical Experience 
 
ACADIA has initiated 17 clinical trials of pimavanserin.  Fifteen of these studies are completed 
and 2 studies are ongoing (Study ACP-103-010 and Study ACP-103-015).  Of the 15 completed 
studies, 14 have been analyzed; analysis is ongoing for the other study (ACP-103-014).  The 2 
ongoing studies, Study ACP-103-010 and Study ACP-103-015, are open-label safety trials.  A 
total of 882 subjects have had exposure to pimavanserin. Of these subjects, 447 were PD/PDP 
patients, 258 were healthy volunteers and 177 were schizophrenic patients.  In a long-term, open-
label safety trial in PDP patients (Study ACP-103-010), 23 subjects have received pimavanserin 
for > 12 months, including 13 subjects treated for ≥ 24 months and 2 subjects treated for > 60 
months.  As of May 1st, 2010, both those subjects remain active. 
 
In the other long-term, open-label safety trial in PDP subjects (ACP-103-015), 77 subjects have 
received pimavanserin for > 12 months and 6 subjects have received pimavanserin for > 24 
months.  As of May 1st, 2010, 160 subjects remain active. 
 
All studies have been, or are being, conducted in accordance with Good Clinical Practice, the 
ethical principles that have their origin in the Declaration of Helsinki, and applicable local 
regulatory requirements. 


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Across study populations (healthy volunteers as well as patients), pimavanserin has been shown 
to be generally safe and well tolerated at single doses up to 300 mg and multiple doses up to 160 
mg. The most common adverse events (AEs) were similar in healthy normal volunteers, PD 
patients, and schizophrenia patients and occurred at a similar frequency between pimavanserin- 
and placebo-treated subjects. The majority of AEs reported in studies to date were considered 
mild to moderate in nature.  
 
Central nervous system and gastrointestinal disturbances were the most common AEs. Central 
nervous system events included headache, postural dizziness, somnolence (drowsiness), and 
dizziness. Gastrointestinal disturbances included nausea, constipation, dyspepsia, and vomiting; 
severe nausea and vomiting occurred and were dose-limiting in a few cases. Other reported, but 
less common, AEs included psychiatric conditions such as confusion and hallucinations. 
Cardiac-related and cardiovascular AEs were infrequent and included ventricular tachycardia, 
bradycardia, and vasovagal and syncopal episodes. Other infrequent AEs included orthostatic 
hypotension, asthenia, fatigue, peripheral edema, and injury especially due to a fall. 
 
 
 
 
 
  Although the number of SAEs in the 
Parkinson’s disease patients who received pimavanserin may appear disproportionately high, this 
group reflects subjects who participated in the long-term open label safety extension studies 
where duration of dosing is markedly longer than in the other groups. 
 
1.3 
Rationale for the Study 
Given the persistent and progressive nature of PDP, an active therapeutic intervention is needed 
that could effectively manage psychotic symptoms without reducing control of motor function or 
increasing the risk for sedation, hematologic disorders, significant cardiovascular events, or 
mortality in this older and fragile patient population.  
 
Like all of the atypical antipsychotics, pimavanserin shows high potency and efficacy as a 
competitive antagonist and inverse agonist at the 5-HT2A receptor. Importantly for its potential 
use in PD subjects, pimavanserin has no affinity or functional activity at D2 receptors. Thus, 
pimavanserin may offer antipsychotic benefit in this subject population with an acceptable risk 
profile. Results of previously completed trials of pimavanserin in PDP indicate that pimavanserin 
reduced psychosis without worsening motor function.  These data support the continued 
development of pimavanserin for the treatment of PDP. 
 
ACADIA Pharmaceuticals Inc. (ACADIA) is currently planning to conduct additional double-
blind, placebo-controlled studies to assess the efficacy and safety of pimavanserin in the 
treatment of PDP.   
 


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2. 
OBJECTIVES 
 
Primary Objective:  
• To assess long-term safety and tolerability of pimavanserin for the treatment of PDP  
 
3. 
STUDY DESIGN 
3.1 
Overall Study Design 
Pimavanserin will be administered once daily at a fixed dose level of 40 mg.  The study will be 
conducted on an outpatient basis.   
 
Subjects who have completed the treatment period of a previous blinded study of pimavanserin 
in PDP subjects and who may, in the opinion of the Investigator, benefit from continued 
treatment with pimavanserin will be enrolled in this study for safety evaluation.  Subjects may be 
enrolled in this study as early as the last visit of the treatment phase of the previous study OR up 
to 28 days following completion of the treatment period.  
 
Subjects will be required to visit the clinic on Week 2 (Day 14 ± 3 days), Month 1 (Day 28 ± 3 
days), Month 3 (Day 84 ± 7 days), Month 6 (168 days + 7 days), Month 9 (252 days + 7 days), 
Month 12 (336 days + 7 days) and every six months thereafter (every 168 days ± 7 days).  
Unscheduled clinical evaluations may occur at anytime if deemed appropriate by the 
Investigator.  If the subject terminates the study at any time other than a planned visit the subject 
will be required to visit the clinic for an end-of-study evaluation.   
 
3.2 
Dose Rationale  
 
In previous studies of pimavanserin in the PDP population, doses of 20 mg and 40 mg of 
pimavanserin have demonstrated a consistent signal of efficacy across a number of measures, 
including the SAPS, CGI-I, SCOPA nighttime sleep measure and caregiver burden scale. 
Additionally, current long-term open-label studies of pimavanserin in PDP have demonstrated 
that pimavanserin is safe and tolerable at doses of 40 mg and 60 mg.  Thus, 40 mg pimavanserin 
was chosen for this study. 
 
3.3 
Study Duration 
The duration of treatment for any individual subject will be determined based on clinical 
grounds, but may continue for as long as pimavanserin is considered to be tolerated and 
beneficial, or until such time as pimavanserin is approved and commercially available. 


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3.4 
Number of Subjects 
This study may include any eligible subject (as specified in Section 4.1) that completed the 
blinded treatment period of a previous study of pimavanserin in PDP subjects.  At least 400 
subjects are anticipated to be enrolled into ACP-103-015.       
3.5 
Administration of Pimavanserin 
Pimavanserin will be supplied as 20 mg tablets.  Subjects will take a total daily dose of 40 mg 
once daily, administered orally as two 20 mg tablets.  
3.6 
Study Procedures 
Before any subjects may be enrolled in the study, ACADIA and/or designee must obtain a copy 
of essential documents including the following: 
 
• Institutional Review Board (IRB) or Ethics Committee (EC) approval of the protocol and 
Investigator’s Brochure 
• IRB- or EC-approved Informed Consent Form (ICF) 
• Health Insurance Portability and Accountability Act (HIPAA) form (where appropriate) 
• Other documents required by local regulations, as applicable 
 
Each subject and their caregiver must sign the approved ICF and, where appropriate, HIPAA 
forms during the Baseline visit.  Study eligibility will be assessed at the Baseline visit (Visit 1). 
Each subject who meets all eligibility criteria will be assigned a unique identification number. 
No subject will be enrolled twice in the study. Once the identification number has been assigned 
to a subject, no attempt should be made to use that number again. 
 
3.6.1. 
Schedule of Events and Assessments 
Table 1 displays the schedule of events and assessments. 
 
This study will be conducted on an outpatient basis.  Subjects may be enrolled in this study as 
early as the last visit of the treatment period of the previous blinded study of pimavanserin in 
PDP OR up to 28 days following completion of the treatment period of the previous study.   
Subjects who enroll in ACP-103-015 within one week from completion of their participation in 
the previous blinded study should have completed all safety and efficacy assessments for the 
final Study Day as detailed in the previous study.  In addition, subjects must be eligible for 
participation in this study and sign an informed consent form as required at the Baseline visit 
(Day 1) of this study.  These subjects will NOT be required to complete a full Baseline visit as 
detailed in the Schedule of Events and Assessments.   
 
Subjects who are enrolled greater than one week following completion of the previous blinded 
study of pimavanserin for PDP will be required to complete a baseline evaluation that will 
include subject eligibility, an updated medical history, vital signs, weight, a physical exam, 
clinical laboratory tests, pregnancy test, a 12-lead electrocardiogram (ECG), adverse event 
questionnaire, and assessment of prior and concomitant medications.  
 


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Subjects will be started on 40 mg of pimavanserin, administered orally, once per day, preferably 
in the morning during the baseline visit.  Dose escalation or reduction will NOT be allowed.     
All subjects will be required to visit the study site at Week 2, Month 1, Month 3, Month 6, 
Month 9, Month 12 and every six months thereafter to complete safety and clinical evaluations.  
Unscheduled clinical evaluations may occur at anytime if deemed appropriate by the 
Investigator. If the subject terminates the study at any time other than a planned visit the subject 
will be required to visit the clinic for an end-of-study evaluation.   


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Table 1: Schedule of Events and Assessments  
  
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Baseline1 
(Day 1) 
 Week 2 
Day 14     
± 3 days 
 Month 1 
Day 28      
± 3 days 
Month 3 
Day 84 
+ 7days 
Month 6 
Day 168 
+ 7days 
Month 9 
Day 252 
+ 7days 
Month 12 
(Day 336 ± 7 days) 
AND 
every 6 months 
thereafter 
(168 days ± 7 days) 
End-of-Study 
(if subject 
withdraws or 
is terminated 
from the 
study) 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X2 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam3 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Labs 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test 
X 
 
 
X 
X 
X 
X 
X 
Plasma PK Sample4 
 
X 
X 
X 
X 
X 
X 
X 
Caregiver Burden Scale 
 
X 
X 
X 
X 
X 
X 
X 
                                                 
1 Subjects that enroll in this study within one week of completion from a previous blinded study of pimavanserin in will only be required to sign an informed consent form, 
complete an update to the medical history that was performed during the screening and baseline visit of the previous study, complete the Baseline RUD-Lite, and receive study 
drug during the baseline visit.  Subjects that enroll greater than one week of completion from the previous blinded study will be required to complete ALL baseline assessments.  
All assessments are to be performed PRIOR to investigational drug administration. 
2 The medical history to be taken at baseline will be an update to the medical history taken during the screening and baseline visits of the previous study.  Any AEs that occur after 
the informed consent is signed and before the first dose of investigational drug is taken are to be recorded in the updated medical history and NOT in the AEs log.   
3 The physical examination performed on Week 2, Month 1, Month 3, Month 6, Month 9, Month 12 and every 6 months thereafter will be an update to the full physical 
examination conducted during either the last visit of the previous study or at Baseline of this study.  
 


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Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Baseline 
(Day 1) 
 Week 2 
(Day 14 ± 
3 days) 
 Month 1 
(Day 28 ± 
3 days) 
Month 3 
Day 84 
+ 7days 
Month 6 
Day 168 
+ 7days 
Month 9 
Day 252 
+ 7days 
Month 12 
(Day 336 ± 7 days) 
AND 
every 6 months 
thereafter 
(168 days ± 7 days) 
End-of-Study 
(if subject 
withdraws or 
is terminated 
from the 
study) 
SAPS5 
 
 
X 
 
 
 
 
 
UPDRS Parts II & III6 
 
X 
X 
X 
X 
X 
X 
X 
CGI-S and CGI-I7 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events8 
X 
X 
X 
X 
X 
X 
X 
X 
RUD Lite1, 9 
X 
 
 
 
 
 
X 
X 
Prior/Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Drug 
Administration10 
X 
X 
X 
X 
X 
X 
X 
 
 
4 Plasma samples for determination of pimavanserin levels are to be taken PRIOR to investigational drug administration on study days; on study visit days the subject should NOT 
take the day’s dose of investigational drug at home.  They should wait until they are at the clinical site. 
5 Scale for the Assessment of Positive Symptoms (SAPS) may be administered by a Central Rater Service, 
 
6 Unified Parkinson’s Disease Rating Scale (UPDRS) 
7 Clinical Global Impression scale-Severity (CGI-S) and Clinical Global Impression scale-Improvement (CGI-I) 
 8 Any adverse event that occurs after signing the ICF and before the first dose of investigational drug is to be recorded in the updated Medical History taken on the Baseline visit 
(Day 1).  
9 Subjects will complete the Baseline RUD-Lite at the Baseline Visit and the Follow Up Visit at subsequent visits, where noted. 
10 Investigational drug is to be taken daily; on study visit days subjects should NOT take the day’s dose at home but  should wait until they are at the site and have had blood drawn 
for pimavanserin plasma level determination before taking the day’s dose. 


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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
3.6.2. 
Evaluations by Visit 
An outline of study procedures and evaluations by visit and/or Study Day is provided below.  
Only subjects who completed the treatment period of a previous blinded study of pimavanserin 
for PDP may enter this study. 
 
3.6.2.1. 
Visit 1 (Baseline – Day 1)  
For each subject who is enrolling in this study, the following procedures are to be performed 
following completion of the previous blinded study: 
 
 Informed Consent 
 Inclusion/Exclusion Criteria 
 Administration of study drug (subject’s must complete all Baseline assessments prior to 
administration of study drug)  
 Medical History, an update to the medical history taken during the screening and baseline 
visits of the previous study 
 Baseline RUD Lite  
 
In addition, the following procedures are to be performed for each subject who is enrolling in 
this study greater than one week and within 28 days following completion of the previous 
blinded study. 
 
 Weight 
 Vital Signs 
 Physical Examination  
 Clinical Laboratory Tests 
 Serum Pregnancy Test, if applicable 
 12-Lead ECG 
 Baseline RUD Lite 
 Adverse events 
 Prior/Concomitant Medications 
3.6.2.2. 
Visit 2 (Study Week 2 - Day 14 ± 3 days) 
 Weight 
 12-Lead ECG 
 Vital Signs  
 Updated Physical Examination 
 Clinical Laboratory Tests 
 Blood sample for determination of pimavanserin plasma concentration  
 Caregiver Burden Scale 
 UPDRS Parts II and III 
 CGI-S and CGI-I 
 Adverse events 
 Concomitant Medications 
 Administration of study drug  


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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
 
3.6.2.3. 
Visit 3 (Study Month 1 -Day 28 ± 3 days) 
 Weight 
 12-Lead ECG 
 Vital Signs 
 Updated Physical Examination 
 Clinical Laboratory Tests 
 Blood sample for determination of pimavanserin plasma concentration  
 Caregiver Burden Scale 
 Scale for the Assessment of Positive Symptoms (SAPS)  
 UPDRS Parts II and III 
 CGI-S and CGI-I 
 Adverse events 
 Concomitant Medications 
 Administration of study drug 
3.6.2.4. 
Visit 4 + [Study Month 3 (Day 84 ± 7 days) and every 3 months thereafter (every 
84 days ± 7 days) until Month 12 (336 days ± 7 days); then every 6 months 
thereafter (every 168 days ± 7 days)] 
 Weight 
 12-Lead ECG 
 Vital Signs 
 Updated Physical Examination 
 Clinical Laboratory Tests 
 Serum pregnancy test, if applicable 
 Blood sample for determination of pimavanserin plasma concentration  
 Caregiver Burden Scale 
 UPDRS Parts II and III 
 CGI-S and CGI-I 
 Follow Up RUD Lite (only for subjects with a previously performed Baseline RUD Lite 
assessment at the Baseline Visit) 
 Adverse events 
 Concomitant Medications 
 Administration of study drug 
3.6.2.5. 
End-of-Study Visit 
Subjects may be removed from this trial at anytime. Upon termination of the subjects’ 
enrollment in this study an End-of-Study visit will be scheduled and the following procedures 
will be conducted: 
 
 Weight 
 12-Lead ECG 
 Vital Signs 
 Physical Examination  
 Clinical Laboratory Tests 


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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
 Serum Pregnancy Test, if applicable 
 Plasma collection for pimavanserin determination 
 Caregiver Burden Scale 
 UPDRS Parts II and III 
 CGI-S and CGI-I 
 Follow Up RUD Lite (only for subjects with a Baseline RUD Lite assessment at the 
Baseline Visit) 
 Adverse events 
 Concomitant Medications 
 
4. 
SELECTION OF SUBJECTS AND CRITERIA FOR WITHDRAWAL 
4.1 
Selection of Subjects 
The study population is defined as subjects who meet the following criteria: 
 
Inclusion Criteria: 
1. Subject has completed the blinded treatment period of a previous study of pimavanserin 
in PDP within the last 28 days and, who may, in the opinion of the Investigator, benefit 
from therapy with pimavanserin  
2. Subject must have clear sensorium at study entry (i.e., oriented to time, person, and 
place) and thus not be delirious  
3. Female subjects must be of non-childbearing potential (defined as either surgically 
sterilized or at least 1 year post-menopausal) or must agree to use a clinically acceptable 
method of contraception (such as intrauterine device [IUD], diaphragm, or oral, injectable 
[e.g. Depo-Provera] or implantable contraception [e.g. Norplant System]) during the 
study and one month following completion of the study 
4. The subject is willing and able to provide consent  
5. Caregiver is willing and able to provide consent and agrees to accompany the subject to 
all visits 
 
Exclusion Criteria: 
1. Subject has current evidence of a clinically significant concurrent medical illness 
including: severe cardiac disease (recent myocardial infarction, congestive heart failure 
or cardiac syncope), severe pulmonary disease (chronic obstructive pulmonary disease or 
emphysema), renal insufficiency or failure, hepatitis, a recent diagnosis of malignancy 
(excluding basal or squamous cell carcinoma), a serious and or unstable gastrointestinal, 
hematologic or other medical disorder 
2. Subject is using any of the medications prohibited or restricted as described in Appendix 
1 (Prohibited and Restricted Concomitant Medications 


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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
3. Subject is on medications known to prolong the QT interval (as described in Appendix 1)
4. Subject has a baseline electrocardiogram (ECG) with Bazett’s corrected QT (QTcB) of
greater than 460 msec if male or 470 msec if female
5. Subject had an allergy or sensitivity to pimavanserin based on known allergies to drugs of
the same class
6. Subject is judged by the Investigator to be inappropriate for the study
Any waiver of these Inclusion and Exclusion Criteria must be approved in writing by the 
Medical Monitor, on a case-by-case basis, prior to enrolling the subject. 
4.2 
Criteria for Subject Withdrawal 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has the 
right to withdraw from the study at any time and for any reason without prejudice to his or her 
future medical care. 
Subjects may be discontinued or withdrawn from the study for a number of reasons, including 
but not limited to those listed below: 

Adverse events(s) (serious or non-serious)

Disease progression

Subject’s voluntary withdrawal of consent

The Investigator determines that continuation in the study would be detrimental to a
subject’s well-being because of development of a serious illness, any other significant
change in clinical status, or any other compelling medical reason

Subject fails to comply with protocol requirements

At discretion of Sponsor

Lost to follow-up

Death

Female subject becomes pregnant
If a subject withdraws or is terminated from the study, all efforts must be made to complete the 
procedures for End-of-Study (see Table 1). Furthermore, a reason for withdrawal from the study 
must be provided on the appropriate page of the electronic CRF (eCRF) and in the subject’s 
medical record. If the subject terminated due to an AE, this event must be reported in accordance 
with procedures described in Section 6.2.7 (Adverse Events) of this protocol.  Additional visits 
may be scheduled as medically indicated.  
If a subject is withdrawn due to an AE, the Investigator will arrange for a follow-up visit with the 
subject, as appropriate, until the event has resolved or stabilized. Efforts must be made to follow 
the course of the AE and to document its progress and resolution as described in Section 6.2.7 in 
this protocol.  


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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
For subjects who withdraw consent, further information for inclusion in the clinical trial database 
will not be collected, with the exception of information regarding ongoing AEs at the time of 
withdrawal.  
5.
TREATMENTS ADMINISTERED
5.1 
Identity of Investigational Products 
Table 2 displays the characteristics of the investigational products to be taken during this 
study. Table 2: Investigational Products 
Drug 
Pimavanserin 
Administration Form 
Tablet 
Strength 
20 mg 
Route of administration 
Oral 
5.2 
Dosing 
Forty (40) mg pimavanserin (2 x 20 mg tablets) will be administered orally (i.e., by mouth; po) 
once daily according to the previously described schedule (see Table 1).  The subject should 
make every attempt to take the investigational product in the morning. 
5.3 
Concomitant Therapy 
Concomitant medications should be kept to a minimum during the study.  The Investigator 
should use such medications in accordance with accepted clinical practice and only medications 
essential for subjects’ well-being while enrolled in the study should be administered at the 
Investigator’s discretion. If such medication is deemed essential, subjects should stay on their 
usual medication regimens at stable doses during the entire course of the study if possible. A 
suitable alternative may be used if the drug is on the prohibited list, based on having a 
consultation with the Medical Monitor prior to such a decision. 
Any treatment given, other than the investigational drug, is to be considered a concomitant 
medication. The dosage, time and reason for taking the concomitant medication should be noted 
in the eCRF and medical notes for all subjects. 
As stated above, the Investigator should examine the acceptability of all concomitant therapy not 
explicitly prohibited in this protocol. In order to assure that appropriate concomitant therapy is 
administered, it is essential that subjects be instructed not to take any medication (either self-
administered non-prescription drugs or prescription therapy prescribed by another physician) 
without prior consultation with the Investigator. Accordingly, each subject will be instructed to 
refrain from drinking alcoholic beverages in excess, and using illicit drugs. Use of other drugs 
including any herbal or over-the-counter preparations should be discussed with Investigator.  


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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
5.3.1. 
Prohibited and Restricted Medications 
The restrictions on concomitant medications outlined in Appendix 1 should be followed during 
the course of the study. 
Appendix 1 does not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor. 
5.4 
Investigational Drug Handling 
5.4.1. 
Test Article 
Pimavanserin (pimavanserin tartrate) is a white to off-white colored powder.  Pimavanserin will 
be provided as 20 mg strength tablets.  ACADIA Pharmaceuticals will supply the pimavanserin 
tablets.   
5.4.2. 
Drug Packaging 
Study medication will be packaged in individual study kits.  Each kit will contain 12 individually 
labeled bottles.  Each bottle will contain 10 days of study drug (20 tablets.)  
5.4.3. 
Dosage and Administrations 
All subjects will take a single oral dose per day (two tablets per dose) of study medication 
(pimavanserin) every day throughout the study.  On study visit days subjects should NOT take a 
dose at home.  The study drug will be administered at the site once the subject has had blood 
drawn for pimavanserin plasma level determinations.  Subjects should not crush, break, chew, 
or dissolve the tablets. 
5.4.4. 
Receipt of Supplies 
The Investigator and/or study staff is responsible for taking an inventory of each shipment of 
investigational drug received and comparing it with the accompanying Drug Accountability 
Report/Material Shipping Form. The Investigator or study staff member will verify the accuracy 
of the information on the form, sign and date it, and return the form to 
 as 
directed. All investigational drug supplied is for use only in this study and should not be used for 
any other purpose.   
5.4.5. 
Storage of Investigational Drug 
The investigational drug must be kept in a securely locked area with restricted access; and stored 
at room temperature, between 20 and 25º C (68 and 77º F.). Neither the Investigator, nor the 
pharmacist, nor any of his/her designees may provide investigational drug to any person not 
participating in the study.  


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5.4.6. 
Record of Dispensing 
Accurate recording of all investigational drug administration for individual subjects will be made 
in the appropriate section of the subject’s CRF. A summary of investigational drug 
administration will appear in the Site Investigational Drug Dispensing and Reconciliation Form. 
This form must be updated as subjects are dispensed study drug and contain the following 
information:  
 The initials and subject number to whom the investigational drug was dispensed; 
 The date(s) and quantity of the investigational drug dispensed to the subject; and 
 The initials of the person dispensing the investigational drug.  
 
5.4.7. 
Accountability 
The Investigator or pharmacist will keep accurate records of the quantities of the investigational 
drug product dispensed, used, and returned by each subject to assure the health authority and 
ACADIA that the investigational drug is not dispensed to any person who is not a subject under 
terms and conditions set forth in this protocol. 
 
At the conclusion of the study, final investigational drug reconciliation will be conducted at the 
site. Final investigational drug accountability documentation will be maintained at both the site 
and at ACADIA. Any unused investigational drug will be returned to 
for destruction 
according to local regulations and standard operating procedures (SOPs).  Documentation of 
investigational drug destruction will be recorded and maintained at the site. 
 
6. 
ASSESSMENT OF SAFETY 
6.1 
Primary Objective 
The primary objective of this study will be to assess long-term safety and tolerability of 
pimavanserin in subjects with PDP as measured by AEs, clinical laboratory tests, ECG, vital 
signs, and physical examinations. Furthermore, results of the safety assessments will be used 
during the conduct of the trial to monitor and protect the safety of enrolled subjects. Information 
regarding safety monitoring can be found within the sections below. 
 
6.2 
Description of Safety Assessments 
6.2.1. 
Updated Medical History   
An updated medical history will be obtained at the baseline visit (Study Day 1) for all subjects. 
Family members, caregivers and/or other persons who know the subject may also be 
interviewed, provided the subject consents, in order to obtain updated information about a 
subject’s current medical and psychiatric conditions.  A careful review of medications that were 
started following completion in the previous pimavanserin study should be obtained. 
 


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6.2.2. 
Physical Examinations and Updated Physical Examinations 
A full physical examination will be performed for those subjects that enroll in this study greater 
than one week following completion of the previous blinded study during the baseline visit by a 
qualified, licensed Doctor of Medicine (MD), Doctor of Osteopathy (DO), or physician assistant 
(PA).  An updated physical examination will be performed for all subjects that enroll in this 
study at the Week 2 visit, Month 1 visit, Month 3 visit, Month 6 visit, Month 9 visit, Month 12 
visit and every 6 month visit thereafter.  At an End-of-Study visit, if a subject withdraws or is 
terminated from the study, a full physical examination will be performed.   
 
A review of systems (ROS) will be included as part of the physical examination procedures. The 
ROS should include:  
 
 Skin, hematological, cardiovascular, pulmonary, gastrointestinal, reproductive, 
neurological, psychiatric, lymphatic, endocrine, musculoskeletal, and/or drug allergies.  
 Particular emphasis should be placed on careful elucidation of hematological, cardiac and 
cardiovascular, neurological and psychiatric conditions. 
 
Findings will be documented in the subject's medical record and on the appropriate eCRF pages. 
Any significant changes from Day 1 (Baseline) are to be recorded during the updated physical 
examination and on the adverse event page for those subjects that enroll greater than one week 
following completion of previous study.  Any significant changes from the last visit of the 
previous study are to be recorded during the updated physical examination and on the adverse 
event page for those subjects that enroll within one week following completion of previous 
study.   
 
6.2.3. 
Weight 
Weight will be measured for those subjects that enroll in this study greater than one week 
following completion of the previous blinded study during the baseline visit, and recorded on the 
appropriate eCRF pages at the Day 1 visit (Baseline).  In addition, weight will be measured for 
all subjects during the Week 2 visit, Month 1 visit, Month 3 visit, Month 6 visit, Month 9 visit, 
Month 12 visit and every 6 month visit thereafter, and if a subject withdraws or is terminated 
from the study, at an End-of-Study visit.   
 
6.2.4. 
Electrocardiogram (ECG) 
Standard 12-lead ECG tracings will be performed on Day 1 (Baseline) for those subjects that 
enroll in this study greater than one week following completion of the previous blinded study.  In 
addition, standard 12-lead ECG tracings will be performed for all subjects the Week 2 visit, 
Month 1 visit, Month 3 visit, Month 6 visit, Month 9 visit, Month 12 visit and every 6 month 
visit thereafter, and if a subject withdraws or is terminated from the study, at an End-of-Study 
visit.   
 


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6.2.5. 
Vital Signs 
All vital sign measurements will be performed by appropriately qualified and authorized study 
personnel. Vital signs will be measured and recorded on the appropriate CRF pages on Day 1 
(Baseline) for those subjects that enroll in this study greater than one week following completion 
of the previous blinded study.  In addition, vital signs will be measured and recorded for all 
subjects at the Week 2 visit, Month 1 visit, Month 3 visit, Month 6 visit, Month 9 visit, Month 12 
visit and every 6 month visit thereafter, and if a subject withdraws or is terminated from the 
study, at an End-of-Study visit.  
 
Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), will be measured in 
the same arm at each visit by using a manual or automated sphygmomanometer. The results will 
be recorded in millimeters of mercury (mmHg) on the appropriate CRF pages. Pulse rate will be 
measured in the radial artery in the dominant arm for 30 seconds and will be recorded as beats 
per minute (bpm). Respiratory rate (RR) will be measured and recorded in breaths/minute. Oral 
temperature will be measured using a digital thermometer. 
 
Each time vital signs are measured the following procedures for orthostatic BP and pulse rate 
evaluation should be followed: 
 
After the subject is supine for approximately 5 minutes, BP and pulse rate will be measured and 
the subject will then be instructed to rise to a standing position. BP and pulse rate will be again 
measured 1 minute after standing. 
 
Potentially clinically significant orthostatic findings include:  
 
 SBP drop of 20 mmHg or more 
 DBP drop of 15 mmHg or more 
 Pulse rate increase of 20 bpm or more and/or  
 Emergence of clinical symptoms (e.g., dizziness) after standing. 
 
 
6.2.6. 
Clinical Laboratory Tests 
Clinical laboratory evaluations will be performed and recorded on Day 1 (Baseline) for those 
subjects that enroll in this study greater than one week following completion of the previous 
blinded study.  In addition, clinical laboratory evaluations will be performed for all subjects at 
the Week 2 visit, Month 1 visit, Month 3 visit, Month 6 visit, Month 9 visit, Month 12 visit and 
every 6 month visit thereafter, and if a subject withdraws or is terminated from the study, at an 
End-of-Study visit.  
Clinical Chemistry Serum Tests 
 Sodium, Potassium, Chloride, Phosphorus , Calcium, Carbon dioxide, Blood urea 
nitrogen, Creatinine, Uric acid 
 Alanine Aminotransferase, Aspartate Aminotransferase, Gamma-Glutamyl 
Transpeptidase, Alkaline Phosphatase, Total Bilirubin, Lactate Dehydrogenase 


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 Albumin, Total Protein 
 Creatine Kinase/Creatine Phosphokinase 
Hematology Tests 
 Complete blood count including 
o White Blood Cell Count 
o Complete Differential (Relative and Absolute) 
o Hematocrit, Hemoglobin, Red Blood Cells, Platelets 
 Reticulocyte Count 
Urinalysis 
 Blood, Red Blood Cells, White Blood Cells, Protein, Glucose, Ketones, Specific Gravity, 
pH 
Pregnancy Testing 
 Serum pregnancy testing will be performed on Day 1 (Baseline) for those women 
of childbearing potential that enroll in this study greater than one week following 
completion of the previous blinded study.  In addition, serum pregnancy testing 
for all women of childbearing potential will occur at the Month 3 visit, Month 6 
visit, Month 9 visit, Month 12 visit and every 6 month visit thereafter and, if a 
subject withdraws or is terminated from the study, at an End-of-Study Visit. 
 
6.2.6.1. 
Sample Collection and Bioanalytical Processing 
Venous blood samples for clinical laboratory tests will be collected via venipuncture into 
appropriate blood collection vacuum tubes. A central laboratory will analyze all clinical 
laboratory test samples. Blood samples for clinical laboratory tests should be collected and 
processed according to the SOP of the central laboratory. 
 
Blood samples for pharmacokinetic (PK) analysis will be sent to the central laboratory for 
storage and will be forwarded to 
for PK analysis.  Detailed collection and handling 
instructions will be provided in the study laboratory manual.  The date of PK blood collection 
must be recorded in the subject’s CRF. Each label will state the study number, subject number, 
analyte (plasma), and study day of sample. 
 
6.2.6.2. 
Clinically Important Abnormalities 
The following general procedure will be used to determine whether the investigational drug has 
clinically important effects on evaluated parameters: 
 
 Each subject with values of potential clinical importance should receive appropriate 
medical evaluation. To accomplish this, the Investigator and the Medical Monitor will 
each review every subject’s complete laboratory, vital signs and ECG data, all AE 
records, and any other pertinent sections of the CRF. All correspondence related to each 
subject will be documented. 
 


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Abnormal laboratory test values should be reviewed and interpreted by the Principal Investigator 
or medically qualified Sub-Investigator.  Laboratory test result reports should be signed and 
dated by the reviewing physician(s) for confirmation. Any significant laboratory abnormalities 
that are either serious or unexpected should be promptly reported to the Medical Monitor. The 
diagnosis associated with any clinically significant laboratory abnormality will be recorded as an 
AE on the CRF. If feasible, the AE should be recorded as the underlying abnormality or 
diagnosis (e.g., renal insufficiency) as opposed to the observed deviation in the laboratory result 
(e.g., elevated creatinine). Additional tests and other evaluations required to establish the 
significance or etiology of an abnormal result, or to monitor the course of an AE, may be 
obtained when clinically indicated and with prior approval of the Medical Monitor. In particular, 
if an abnormal result is observed that is not resolved by the final study visit, repeated tests should 
be performed with prior approval until resolution of the abnormality. 
 
6.2.7. 
Adverse Events 
Adverse events will be recorded for all subjects during the Week 2 visit, Month 1 visit, Month 3 
visit, Month 6 visit, Month 9 visit, Month 12 visit and every 6 month visit thereafter, and if a 
subject withdraws or is terminated from the study, at an End-of-Study visit.  
 
Occurrence of AEs after the informed consent is signed and prior to the first administration of 
investigational drug in this study will be recorded as part of the Updated Medical History taken 
on Day 1 (Baseline). Once the first dose of investigational drug is taken on Day 1 any subsequent 
AEs are to be recorded on the CRF page for AEs. 
 
All AEs must be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained or is judged by the investigator to be no longer clinically significant, or until 
the subject is lost to follow-up.  The investigator is responsible for ensuring that follow-up 
includes any supplemental investigations necessary to elucidate as completely as practical the 
nature and/or causality of the AE.  This may include additionally laboratory tests or 
investigations histopathological examinations or consultation with other health care 
professionals. 
 
Investigators are not obliged to actively seek AE information from former study participants.  
However, if the investigator learns of an SAE at any time after a subject has been discharged 
from the study and the event may reasonably be considered related to the use of the study drug, 
the investigator should promptly telephone the Medical Monitor. 
 
6.2.7.1. 
Definitions 
An AE is any untoward medical occurrence or unintended change from the subject’s pre-
treatment condition, including inter-current illness, that occurs during the course of a clinical 
trial after treatment has started, whether considered related to study treatment or not. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  
 


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When possible, AEs should be described by diagnosis and not by symptoms (e.g., “cold” or 
“seasonal allergies” instead of “runny nose”). 
 
The description of each AE should use the following definitions. 
 
Severity 
 
The severity of each AE will be graded on a 3-point scale and reported in detail as indicated on 
the CRF: 
 
 Mild:  easily tolerated, causing minimal discomfort, and not interfering with normal 
everyday activities. 
 Moderate:  sufficiently discomforting to interfere with normal everyday activities. 
 Severe:  incapacitating and/or preventing normal everyday activities. 
 
Relationship to Investigational Drug 
 
The relationship of investigational drug to each AE will be determined by the Investigator by 
using the following definitions: 
 
 Not related:  The event was clearly related to other factors, such as the subject’s clinical 
state, therapeutic interventions, or concomitant medications administered to the subject. 
 Unlikely:  The event was most likely produced by other factors, such as the subject’s 
clinical state, therapeutic interventions, or concomitant medications administered to the 
subject; and did not follow a known response pattern to the investigational drug. 
 Possible:  The event followed a reasonable temporal sequence from the time of 
investigational drug administration; and/or followed a known response pattern to the 
investigational drug; but could have been produced by other factors, such as the subject’s 
clinical state, therapeutic interventions, or concomitant medications administered to the 
subject. 
 Probable:  The event followed a reasonable temporal sequence from the time of 
investigational drug administration; and followed a known response pattern to the 
investigational drug; and could not be reasonably explained by other factors, such as the 
subject’s clinical state, therapeutic interventions, or concomitant medications 
administered to the subject. 
 Highly Probable:  The event followed a reasonable temporal sequence from the time of 
investigational drug administration; and followed a known response pattern to the 
investigational drug; and could not be reasonably explained by other factors, such as the 
subject’s clinical state, therapeutic interventions, or concomitant medications 
administered to the subject; and either occurred immediately following investigational 
drug administration or improved on stopping the investigational drug or reappeared on 
repeat exposure. 
 
Duration 
 
The duration of the AE should be recorded using the following criteria: 


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
Start: Date of the first episode of the AE or date of significant sustained worsening in
severity

Stop: Date when AE either ceased permanently or changed in severity
Frequency 
The duration of the AE should be recorded using the following criteria: 

Single:
Experienced once, without recurrence 

Recurrent:
More than one discrete episode with the same severity 
Action Taken with Investigational Drug 

None:
No change in study drug 

Interrupted:
Investigational drug temporarily stopped 

Discontinued: 
Investigational drug discontinued permanently
Therapy 

None:
No new treatment instituted 

Medication:
New treatment initiated as a direct result of AE 

Other:
Other action required 
Outcome 

Ongoing:
AE has not yet stopped 

Resolved, no sequelae:
Subject has fully recovered 
Resolved, with sequelae:
The AE has stopped, but the subject has a residual 
effect directly related to the AE

Death:
The subject died as a result of the AE 

At Death, ongoing:
AE ongoing at time of subject death 
Seriousness 

Not serious:

Serious:
Does not meet the criteria described in Section 6.2.7.2 
Meets the criteria described  in Section 6.2.7.2 
6.2.7.2. 
Serious Adverse Events 
A SAE is any AE that results in any of the following outcomes: 

Results in death

Is life-threatening (i.e., the subject was at risk of death at the time of the event; it does not
refer to an event which hypothetically might have caused death if it were more severe)

Requires inpatient hospitalization or prolongation of existing hospitalization


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 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly or birth defect 
 Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but based on appropriate medical judgment may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the outcomes 
listed above. 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. 
 
Investigator Reporting Requirements 
All SAEs, whether or not there is a suspected relationship to investigational drug, must be 
reported immediately to 
 (see table below for contact 
details.) In addition, if the Investigator learns of an SAE occurring after a subject withdraws or is 
terminated from the study, but within 30 days after the last administration of the investigational 
drug, he/she should immediately report the event to 
 (see 
contact details below.) 
 
 
Country 
Fax Number 
Phone Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Investigator will complete and submit a SAE Form within 24 hours of discovery for all 
SAEs. The Investigator is obligated to provide information as requested by the clinical monitor 


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in addition to the information listed on the Serious Adverse Event Form. In general, this will 
include a description of the AE in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality. In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible.  
 
In emergency situations, the Investigator should contact the Medical Monitor at 
 
  
 
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. It is the responsibility of the Investigator to report SAEs to
 
within 24 hours of discovery, to allow for the processing of such 
reports to meet regulatory timelines. 
 
Do not delay in the reporting of any SAE in order to obtain additional information. Any 
additional information, if collected, can be reported to the clinical monitor as a follow-up to the 
initial report. SAEs will be reported using the SAE forms provided as part of the subject’s CRF. 
Please remember to provide the subject identification number, subject initials and other 
appropriate terminology and ensure the narrative is comprehensive and includes a chronological 
description and assessment of the event. 
 
The process for reporting an SAE including those that are considered a consequence of 
investigational drug, of overdose, or associated with pregnancy is as follows: 
 
• Complete an SAE form; 
• Complete the narrative which should be comprehensive and include a chronological 
description and assessment of the event; 
• Complete the fax cover sheet and fax the SAE form to
 
• Ensure the SAE is documented in the source documents and that an AE page is created in the 
subject’s eCRF; 
 
For life-threatening or fatal events, the Investigator (or designee) must call the Medical 
Monitor immediately. All SAEs must be reported within 24 hours of discovery by fax to 
.  If it is not possible to fax the SAE form within the 24-hour 
timeframe, the SAE may be reported by telephone.  All contact details are provided in the 
Investigator Site File/Regulatory Binder. 
 
It is the Investigator’s responsibility to notify the responsible IRB/EC regarding new and 
significant safety information, including expedited safety reports. The Investigator will be 
responsible for forwarding any additional information to the IRB/EC in accordance with specific 
agreements and/or local requirements. 
 
Subjects in this study will be followed for any SAEs and/or unexpected events by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. These events 


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should continue to be reported within 24 hours of discovery, particularly life-threatening or fatal 
events, and the Investigator should continue to provide reports to the IRB/EC, as required. In the 
event of any SAE (other than death), the subject will be instructed to contact the Investigator (or 
designee) using the telephone number provided in the subject information sheet. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible following 
the report of the SAE. 
6.2.8. 
Overdose of Investigational Medicinal Product 
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.  
Any events that are the consequence of investigational drug overdose and which meet the criteria 
for a SAE (Section 6.2.7.2) should be reported via the SAE forms. Any case of overdose must be 
treated according to the current medical practice and followed until resolution or until the 
subject’s condition is considered stable. 
6.2.9. 
Pregnancy 
Any subject who becomes pregnant (with or without AEs) should be reported on the Clinical 
Trial Pregnancy form. This form should be sent to 
 (see 
contact details in Section 6.2.7.2). Any subject who becomes pregnant during the study must 
be withdrawn from treatment and will be followed until delivery or termination of pregnancy. 
Any events that are the consequence of pregnancy and which meet the criteria for serious 
(Section 6.2.7.2) should also be reported via the SAE forms provided and according to the 
directions in Section 6.2.7.2. 
6.2.10. Emergency Treatment 
During and following a subject’s participation in the trial, the Investigator/institution should 
ensure that adequate medical care is provided to a subject for any AEs, including clinically 
significant laboratory values, related to the trial. The Investigator/institution should inform a 
subject when medical care is needed for intercurrent illness(es) of which the Investigator 
becomes aware.  
7.
CLINICAL EVALUATIONS
7.1 
Scale for Assessment of Positive Symptoms (SAPS) 
This scale will be administered to all subjects during Study Month 1 Visit 4. The SAPS 
(Andreasen, 1984) was designed to measure positive psychotic symptoms, especially in 
schizophrenia.  Positive symptoms include delusions, hallucinations, abnormalities in language 
and behavior, and disordered thought processes. Two of the SAPS subscales, Hallucinations and 
Delusions, will be used in this trial (see Appendix 3). The selection of these domains is based 


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principally on their relevance to the specific symptomatology of the PDP population, their utility, 
as demonstrated in a previous study of pimavanserin in PDP subjects (ACP-103-006) for 
assessing the severity (reflective of frequency and duration) of these symptoms, and their high 
inter-rater reliability.  
At study sites located outside the United States, qualified raters will be trained and certified to 
administer the SAPS.  At U.S. sites, a centralized rating service, 
will conduct the 
SAPS assessment at the Month 1 Visit 4 only.  The centralized rating service is being used to 
control for possible bias in face-to-face ratings, and to obtain a “blinded” rating of subject 
symptom severity and change.  A remote blinded rater (i.e., mental health evaluator) from the 
centralized service will conduct the SAPS using videoconference technology.  The remote rater 
will be blind to the study design, entrance criteria, visit number, and treatment assignment.  The 
videoconferencing technology used to connect the subject with the remote rater will be Polycom 
videoconferencing equipment connected over an IP VPN (Virtual Private Connection). There 
will be no connection or access to or from any other device, including the Public Internet.  These 
combined technologies ensure that the remote assessment is conducted in privacy and allows the 
remote rater to assess all aspects of the SAPS. 
Subjects whose SAPS ratings are being conducted by 
will be asked to give informed 
consent to have their assessments recorded.  The recordings will be used for training and/or 
quality control purposes by
  The recordings can only be listened to and/or viewed 
by the employees or consultants of 
  No other person will have access to the 
recordings, to the extent permitted by law.  Subject names or other identifying information will 
not be used in training records or publications.  A unique code number that is assigned to the 
subjects will identify their recordings.  The recordings will be maintained in a locked area with 
limited access.  The recordings will be erased no later than one (1) year after the study ends.  
Subjects can still participate in the study even if they choose not to have their assessments 
recorded. 
7.2 
Unified Parkinson’s Disease Rating Scale (UPDRS) 
Motor function will be evaluated by completing Parts II and III of the UPDRS assessment.  
Note:  the UPDRS assessments are to be conducted in the “on” state.  This will ensure that noise 
associated with a subject’s “on/off” status does not confound interpretations of the motor 
function data. 
The UPDRS is a comprehensive battery of motor and behavioral indices derived from the 
Columbia Scale (Fahn et al., 1987; Appendix 4), providing explicit rating criteria that have 
undergone considerable testing for reliability.  Parts II and III will be administered to all subjects 
at the Week 2 visit, Month 1 visit, Month 3 visit, Month 6 visit, Month 9 visit, Month 12 visit 
and  every 6 month visit thereafter, and if a subject withdraws or is terminated from the study, at 
an End-of-Study visit.  


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7.3 
Clinical Global Impression Scale (CGI) 
The CGI allows the Investigator to determine, in a global sense, how severely psychotic these 
subjects are in the context of other PD subjects using the CGI-S and how much improvement is 
seen using the CGI-I. This instrument is a reliable scale that allows the Investigator to ignore 
baseline dementia, personality traits, and a “reasonable” degree of anxiety that usually 
accompanies clinical motor fluctuations and other peculiar aspects of PD. The CGI scale appears 
in Appendix 5. 
These scales (CGI-S and CGI-I) will be administered to all subjects at the Week 2 visit, Month 1 
visit, Month 3 visit, Month 6 visit, Month 9 visit, Month 12 visit and every 6 month visit 
thereafter, and if a subject withdraws or is terminated from the study, at an End-of-Study visit. 
7.4 
Caregiver Burden Scale 
The Caregiver Burden Scale (Appendix 2) will be administered to the subject’s attending 
caregiver at the Week 2 visit, Month 1 visit, Month 3 visit, Month 6 visit, Month 9 visit, Month 
12 visit and every 6 month visit thereafter, and if a subject withdraws or is terminated from the 
study, at an End-of-Study visit.  This self-administered 22-item questionnaire is commonly used 
in caregivers of the dementia patient population, most specifically in caregivers of subjects with 
Alzheimer’s disease.  Nonetheless, it has been reported to have high reliability in PD (Aarsland 
et al., 1999).  
7.5 
RUD Lite 
Data related to the health economics and burden of illness of PDP are sparse.  In fact, there are 
no instruments specifically developed to capture this information in the PDP patient population.  
The Resource Utilization in Dementia (RUD) instrument was originally developed for use in 
patients with dementia to capture the use of resources by patients during the course of a clinical 
trial (Wimo et al., 1998).  The assessment of both formal and informal resource use of the patient 
and primary caregiver makes it possible to calculate costs from a societal perspective.  The RUD 
and RUD Lite have been used in several completed and ongoing clinical trials of investigational 
drugs, and are the most widely used instruments for the collection of resource use data in 
dementia (Appendix 6). 
The RUD Lite is an adaptation of the full RUD and is designed to decrease the time burden 
associated with completing multiple assessments during the typical clinical study visit.  For the 
purposes of this study, the RUD Lite instrument has been further adapted to make it compatible 
with the PDP patient population.  It is administered as a structured interview with the primary 
caregiver or other person with knowledge about the patient situation.  The validity and reliability 
of the RUD instrument has been investigated in the residential care setting as well as community 
care setting (Wimo & Nordberg, 2007; Wimo et al., 2003a,b).  Its application in other diseases, 
including PDP, has not been studied; however, it has good face validity and is readily adaptable 
for use in other chronic disorders in older age-groups involving a substantial component of 
informal care. 


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The RUD Lite assessment contains a Baseline version and a Follow Up Version. Table 1: 
Schedule of Events and Assessments describes which version should be used at the specified 
study visits. 
8.
ASSESSMENT OF PHARMACOKINETICS
Blood samples will be collected at the Week 2 visit, Month 1 visit, Month 3 visit, Month 6 visit, 
Month 9 visit, Month 12 visit and every 6 month visit thereafter, and if a subject withdraws or is 
terminated from the study, at an End-of-Study visit prior to administration of investigational drug 
on those days. Details of the time of administration of the prior day’s dose together with the time 
of sample collection will aid the interpretation of the concentration data. Section 6.2.6.1 includes 
additional information regarding PK sample collection and bioanalytical processing. 
Pharmacokinetic data will be summarized descriptively. If appropriate, data will be further 
stratified by age, gender, and/or other demographic variables. As appropriate, graphic summaries 
of the PK data will be prepared. 
9.
DATA RECORDING, RETENTION, AND MONITORING
9.1 
Case Report Forms 
An electronic CRF will be provided for each subject and will be used to record all the protocol-
required information to be reported on each subject. The Investigator will maintain a log of the 
source documents from which the information on the CRF will be derived. This will include 
identification of any data agreed with ACADIA to be recorded directly in the CRFs, i.e. where 
the CRF will be considered the source of the information. The participants of the study will not 
be identified by name on the CRF or any other study documents to be collected by ACADIA 
and/or designee, but will be identified by a Subject Identification Number and initials. 
All clinical information requested in this protocol will be recorded on the CRFs provided by 
ACADIA and/or designee using legible entries via computer.  All corrections will be captured 
electronically in the audit trail in addition to the date/time stamp and the user id.  
All CRFs must be reviewed and verified for accuracy by the Investigator and signed off. A copy 
(or original) of the CRF will be kept at the Investigator’s site at the completion of the study. 
9.2 
Availability and Retention of Records 
The Investigator and institution must permit authorized representatives of ACADIA and/or 
designee (including monitors and auditors), and the regulatory agency(s) (including inspectors), 
and the IRB 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 CRF was derived. 


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Investigators are required to maintain all essential study documentation as per ICH Good 
Clinical Practice (GCP). This includes, but is not limited to, copies of signed, dated and 
completed CRFs, documentation of CRF corrections, signed ICFs, subject-related source 
documentation, and adequate records for the receipt and disposition of all investigational drug. 
Investigators should maintain all essential study documentation, for a period of at least two years 
following the last approval of marketing application in an ICH region (U.S., Europe and Japan), 
or until at least two years after the drug investigational program is discontinued, unless a longer 
period is required by applicable law or regulation. Only ACADIA can notify an Investigator 
when any records may be discarded. Investigators should contact ACADIA before destroying 
any files. 
 
9.3 
Quality Control and Quality Assurance 
ACADIA and/or designee representatives and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, upon 
request, inspecting the various records of the trial (e.g., CRFs and other pertinent data) provided 
that subject confidentiality is respected. 
 
The ACADIA and/or designee monitor is responsible for inspecting the CRFs 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 CRFs. 
 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are resolved. 
 
In accordance with ICH Guidance on GCP and ACADIA’s audit plans, this study may be 
selected for audit. Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories, 
etc.) and review of study-related records will occur in order to evaluate the trial conduct and 
compliance with the protocol, ICH Guidance on GCP, and applicable regulatory requirements. 
 
9.4 
Subject Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. On 
the CRFs or other documents submitted to ACADIA and/or designee, subjects must be identified 
by their initials and a Subject Identification Number only. Documents that are not for submission 
to ACADIA and/or designee (e.g., signed ICFs) should be kept in strict confidence by the 
Investigator in compliance with Federal regulations or other applicable laws or ICH Guidance on 
GCP. 
 
ACADIA and/or designee representatives, regulatory authority inspectors and IRB 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 


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10. 
STATISTICAL PLAN  
Statistical methods will be documented in detail in a Statistical Analysis Plan to be reviewed and 
approved by ACADIA before any planned database locks. 
10.1 
General Statistical Methods  
All analyses will be performed using SAS V8 (SAS Institute, Inc., Cary, North Carolina). 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analysis of the data from this study will follow appropriate SOPs. 
10.2 
Study Subjects 
10.2.1. Analysis Population(s) 
The safety population will consist of all subjects who were enrolled in this study and received at 
least one treatment application. The safety population will be used for all safety analyses. 
10.2.2. Subject Accountability and Subject Disposition  
Study enrollment by center will be summarized by the number and percentage of subjects who 
completed the study and those who withdrew early will be presented. A breakdown of the 
corresponding reasons for early withdrawal from study will be provided. 
11. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic variables include: age, sex, race, and weight.  Other baseline characteristics 
include medical history.     
12. 
SAFETY ANALYSIS 
12.1 
Adverse Events 
All AEs will be coded using the MedDRA coding dictionary. Events will be classified by body 
system and preferred term. All AEs for each subject including the same event on several 
occasions will be listed, giving both preferred term and the original term. Subject incidence rates 
of treatment-emergent AEs will be displayed by system organ class. AEs will also be 
summarized by severity and relationship to study drug. Subject incidence rates of serious AEs 
(including deaths) will also be displayed.   
 
12.1.1. Clinical Laboratory Values 
Serum clinical chemistry, hematology and urinalysis results will be classified as normal or 
abnormal.  
 
12.1.2. Vital Signs   
Summary statistics of absolute values and percent change from Day 1 (Baseline)  will be 
provided for BP (DBP and SBP), pulse rate, and RR. All values outside a predefined normal 
range will be flagged in the individual subject data listings. 
 


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12.1.3. Electrocardiogram 
A 12-lead ECG will be recorded at Day 1 (Baseline) for those subjects that enroll greater than 
one week following completion of the previous study.  All subjects will have an ECG at every 
study visit.  Subjects who terminate early will also have an ECG at the End-of-Study visit.  
 
12.1.4. Physical Examinations 
Subjects who enroll in the study greater than one week following completion of the previous 
study will undergo a full physical examination at Day 1 (Baseline). All subjects in the study will 
undergo an updated physical examination at every study visit.  A full physical examination will 
be conducted for all subjects who withdraw or are terminated from the study at an End-of-Study 
visit.  Physical examination data will be included in data listings and reviewed for any clinically 
significant abnormalities. 
 
12.1.5. Pharmacokinetic Analysis 
Pharmacokinetic data will be summarized descriptively.  If appropriate, data will be further 
stratified by age, gender, and/or other demographic variables.  As appropriate, graphic 
summaries of the PK data will be prepared. 
 
12.2 
Efficacy Analysis 
No formal statistical analysis is currently planned for the clinical rating scales (SAPS, UPDRS, 
CGI-I, CGI-S and Caregiver Burden Scale) recorded in this study; however, results for the safety 
population will be summarized with descriptive statistics at each study visit.    
  
13. 
REGULATORY COMPLIANCE 
13.1 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, the Declaration of Helsinki, ICH 
principles of Good Clinical Practice, and other applicable regulatory requirements. 
 
13.2 
Regulatory Approval 
The Investigator at each site is responsible for obtaining IRB or EC approval for the final 
protocol, sponsor-approved ICF, and any advertisements to recruit subjects. Written approval of 
these documents must be obtained from the committee before any subject is enrolled at a center. 
 
The Investigator is also responsible for the following interactions with the IRB or EC: 
 
 Obtaining IRB or EC approval, as appropriate, for any protocol amendments and ICF 
revisions before implementing the changes; 
 Providing the IRB or EC with any required information before or during the study; 


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 Submitting progress reports to the IRB or EC, as required, during the conduct of the 
study; 
 Requesting re-review and approval of the study, as needed; 
 Providing copies of all IRB or EC re-approvals and relevant communication to ACADIA 
and/or designee; 
 Notifying the IRB or EC of all serious and unexpected AEs related to the investigational 
drug reported by ACADIA and/or designee, as required. 
 
13.3 
Subject Informed Consent 
Prior to any study-related activities, an IRB- or EC-approved ICF (and HIPAA authorization 
where applicable) must be signed and dated by the subject and the caregiver. The Informed 
Consent must at a minimum include the elements of consent described in the ICH guidance on 
GCP and the U.S. Code of Federal Regulations 21CFR§50.25. 
 
The Investigator’s draft Informed Consent must be reviewed and approved by ACADIA and/or 
designee prior to IRB or EC submission The Investigator’s IRB or EC will review and approve 
the study protocol, ICF, HIPAA authorization and any other study document (s) according to 
local regulations. After approval by the IRB or EC committee, the following documentation will 
be sent to ACADIA or designee before the study commences: 
 
 Confirmation of IRB or EC approval of the protocol 
 Confirmation of IRB or EC approval of the ICF 
 Confirmation of IRB or EC approval of the HIPAA authorization 
 
In addition to the written ICF, it is the responsibility of the Investigator to ensure that each 
subject under consideration for inclusion into the study be given a verbal explanation of the 
nature, purpose, risks and requirements of the trial. Subjects must be given an adequate 
opportunity to ask the Investigator questions about any aspects of the trial. Once the subject has 
read the ICF, discussed it with the Investigator, and has agreed to participate, he/she will be 
asked to sign the informed consent (and HIPAA authorization, where applicable). The original, 
signed Informed Consent Form (ICF) and HIPAA authorization will remain at the site and copies 
will be given to the subject. 
 
The subject’s consent is confirmed by the dated signature of the subject and by the dated 
signature of the person conducting the informed consent discussions.   
 
The subject’s caregiver will also be asked to consent to participate in the study.  The Investigator 
will use similar procedures to ensure that the caregiver understands the nature, purpose, risks and 
requirements of the trial.  Caregivers must be given an adequate opportunity to ask the 
Investigator questions about any aspects of the trial prior to signing the ICF. 
 
13.4 
Subject Compensation for Adverse Effects on Health 
ACADIA will adhere to any applicable local regulations regarding Clinical Trial Compensation 
Guidelines to subjects whose health is adversely affected by taking part in the study. 


ACADIA Pharmaceuticals Inc. 
 
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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
 
13.5 
Protocol Amendments and Study Termination 
Protocol amendments must be made only with the prior approval of ACADIA and documented 
approval/favorable opinion of the IRB or EC of an amendment, except where necessary to 
protect the safety, rights, or welfare of subjects. Agreement from the Investigator must be 
obtained for all protocol amendments and amendments to the Informed Consent document. The 
IRB or EC must be informed of all amendments and give approval for any amendments likely to 
affect the safety of the subjects or the conduct of the trial. The Investigator must send a copy of 
the approval letter from the IRB or EC to ACADIA and/or designee.  
 
Both ACADIA and the Investigator reserve the right to terminate the study, according to the 
study contract. The Investigator should notify the IRB or EC in writing of the trial’s completion 
or early termination and send a copy of the notification to ACADIA and/or designee.  
 
13.6 
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. 
 
13.7 
Publication 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
 


ACADIA Pharmaceuticals Inc. 
 
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June 30, 2010 
 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
 
14. 
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 as described in 21 CFR parts 50, 54, 56, and 312 and according to applicable local 
requirements. 
 
Investigator 
 
 
Date:_____________  Signature: ____________________________________________ 
 
 
Printed Name: ___________________________________ 
 


ACADIA Pharmaceuticals Inc. 
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Protocol Amendment #6 ACP-103-015 
June 30, 2010 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
15.
REFERENCES
Aarsland D, Larsen JP, Lim NG, Janvin C, Karlsen K, Tandberg E, Cummings JL (1999). 
Range of neuropsychiatric disturbances in patients with Parkinson's disease. J Neurol 
Neurosurg Psychiatry; 67(4): 492-496 
Andreason, N., Scale for the Positive Assessment of Positive Symptoms. Iowa City, 
IA, University of Iowa, 1984. 
Chou, KL and Fernandez, HH (2006). Combating psychosis in Parkinson's disease 
patients: the use of antipsychotic drugs. Expert Opin Investig Drugs; 15(4): 339-349. 
Factor, S. A., Feustel, P. J., Friedman, J. H., Comella, C. L., Goetz, C. G., Kurlan, R., Parsa, 
M., Pfeiffer, R., (2003). Longitudinal outcome of Parkinson's disease patients with psychosis. 
Neurology; 60(11): 1756-1761. 
Fahn S, Elton RL, and Members of the UPDRS Development Committee (1987). Unified 
Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Lieberman A, eds: Recent 
developments in Parkinson's disease. Florham Park, NJ: Macmillan Health Care Information; pp 
153–163. 
Fenelon G, Mahieux F, Huon R, Ziegler M (2000). Hallucinations in Parkinson's 
disease: prevalence, phenomenology and risk factors. Brain; 123: 733-745. 
Guy, W., ECDEU Assessment Manual for Psychopharmacology – Revised 
(DHEW Publ No ADM 76-338). Rockville MD, U.S. Department of Health, Education, 
and Welfare Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of Extramural 
Research Programs, 1976, p. 218-222. 
Marsh, L. Psychosis in Parkinson's disease. Primary Psychiatry, 2005, 12(7). 
Naidu Y, Schapira AHV, Martinez-Martin P et al, International validation of the first 
comprehensive unified motor symptoms scale (NMSS) for Parkinson’s disease (PD). Mov. 
Disord. 21 (Suppl. 15), P1031 S613 (2006). 
Ondo, W., Tintner, R., Voung, K.D., Lai, D., Ringholz, G. Double-blind, placebo-controlled, 
unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in 
Parkinson’s Disease. Mov Disord, 2005, 20(8):958-63. 
Rabey, JM, Prokhorov T, Miniovitz A, Dobronevsky E, Klein C.  Effect of quetiapine in 
psychotic Parkinson’s disease patients:a double-blind labeled study of 3 months’ duration. Mov 
Disord, 2007, 22(3):313-8. 


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Protocol Amendment #6 ACP-103-015 
June 30, 2010 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Wang, P. S., Schneeweiss, S., Avorn, J., Fischer, M. A., Mogun, H., Solomon, D. H., 
Brookhart, M. A., Risk of death in elderly users of conventional vs. atypical 
antipsychotic medications. N Engl J Med, 2005, 353(22): p. 2335-41. 
Weiner, D. M., Vanover, K. E., Brann, M. R., Meltzer, H. Y., Davis, R. E., 
Psychosis of Parkinson's disease: serotonin 2A receptor inverse agonists as 
potential therapeutics. Curr Opin Investig Drugs, 2003, 4(7): p. 815-9. 
Weintraub, D., and Stern, M.B., Psychiatric Complications in Parkinson Disease. 
Am J Geriat Psych, 2005, 13: 844-851. 
Wimo A, Wetterholm AL, Mastey V, Winblad B.  Evaluation of the resource utilization and 
caregiver time in anti-dementia drug trials – a quantitative battery. In: Wimo A, Karlsson G, 
Jonsson B, Winblad B (eds). The Health Economics of Dementia, 1998. Wiley’s, London, UK. 
Wimo A and Nordberg G (2007). Validity and reliability of assessments of time: Comparisons of 
direct observations and estimates of time by the use of the resource utilization in dementia 
(RUD)-instrument. Arch of Gerontology and Geriatrics; 44: 71-81. 
Wimo A, Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wetterholm AL, Mastey 
V, Haglund A, Zhang R, Miceli R, Chin W, Subbiah P (2003a). An economic evaluation of 
donepezil in mild to moderate Alzheimer’s disease: Results of a 1-year, double-blind, 
randomized trial. Dement Geriatr Cogn Disord; 15: 44-54. 
Wimo A, Winblad B, Stoffler A, Wirth Y, Mobius HJ (2003b). Resource utilization and cost 
analysis of memantine in patients with moderate to severe Alzheimer’s disease. 
Pharmacoeconomics; 21(5): 327-340. 
Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: correlates of feeling of 
burden.  Gerontologist 1980; 20:649-55. 


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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
16. 
APPENDICES 
Page 
 
APPENDIX
 
 1:  PROHIBITED AND RESTRICTED CONCOMITANT MEDICATIONS ...................................... 47
APPENDIX
 
 2: CAREGIVER BURDEN SCALE ....................................................................................................... 48
APPENDIX
 
 3: SCALE FOR THE ASSESSMENT OF POSITIVE SYMPTOMS (SAPS) ....................................... 49
APPENDIX
 
 4: UNIFIED PARKINSON’S DISEASE RATING SCALE (UPDRS) .................................................. 62
APPENDIX
 
 5: CLINICAL GLOBAL IMPRESSION (CGI) SCALES ...................................................................... 72
APPENDIX
 
 6: RESOURCE UTILIZATION IN DEMENTIA (RUD LITE) ............................................................. 73
 


ACADIA Pharmaceuticals Inc. 
 
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Protocol Amendment # 6 ACP-103-015 
 
June 30, 2010 
 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.  
 
APPENDIX 1:  PROHIBITED AND RESTRICTED CONCOMITANT MEDICATIONS 
 
The following is an outline of the restrictions on concomitant medications. Any questions 
regarding prohibited and restricted concomitant medications should be discussed with the 
 Medical Monitor. 
 
1. Antipsychotics are prohibited during the first month of the study, including clozapine, 
quetiapine, risperidone, olanzapine, ziprasidone. Addition of any antipsychotic after the 
first month of the study must be discussed with the Medical Monitor. 
 
2. The following medications are prohibited and must have been discontinued no less than 
30 days prior to Study Day 1:  mianserin, mirtazepine, nefazodone, cyproheptadine, 
fluvoxamine, other investigational agents. 
 
3. Centrally-acting anticholinergic medications are prohibited and must have been 
discontinued no less than 2 weeks prior to Study Day 1. These include, and are not 
limited to, benztropine, biperiden, and trihexylphenidyl.  Anticholinergic agents that act 
predominantly on the peripheral nervous system such as tolteradine or oxybutynin, are 
allowed. 
 
4. Use of acetylcholinesterase inhibitors is allowed. 
 
5. Medications that can prolong QT interval are prohibited. These include, and are not 
limited to the following:- 
• Antiarrhythmic drugs including quinidine, procainamide, disopyramide, ajmaline, 
encainide, flecainide, propafenone, amiodarone, sotalol, d-sotalol, bretylium, 
ibutilide, dofetilide, amakalant, semantilide 
• Anticonvulsants including felbamate, fosphenytoin 
• Antidepressants including amitriptyline, nortriptyline, imipramine, desipramine, 
clomipramine, maprotiline, doxepin 
• Antihistamines including diphenhydramine 
• Antimicrobial and antimalarial drugs including erythromycin, clarithromycin, 
ketoconazole, pentamidine, quinine, chloroquine, halofantrine 
• Antipsychotics including thioridazine, chlorpromazine, haloperidol, pimozide, 
ziprasidone, mesoridazine 
• Others including methadone, cocaine 
 
6. Use of amantadine, which may cause QT prolongation, should be discussed with the 
medical monitor. 

SAP_001.pdf: 
Official Title: A multi-center, open-label extension study to examine the safety and 
tolerability of ACP-103 in the treatment of psychosis in Parkinson’s Disease 
NCT Number: NCT00550238 


-003   
STATISTICAL ANALYSIS PLAN 
Protocol Number: ACP-103-015 
A Multi-Center, Open-Label Extension Study to Examine 
the Safety and Tolerability of ACP-103 in the Treatment of 
Psychosis in Parkinson’s Disease 
ACADIA Pharmaceuticals Inc. 
 
 
Version 1: 18 December 2013 
Version 2:      05 August 2014 
CONFIDENTIAL 


( 
ACADIA 
Pharmaceuticals 
Statistical Analysis Plan Approval Form 
Protocol Number: 
ACP-103-015 
Study Title: 
A Multi-Center, Open-Label Extension Study to Examine the 
Safety and Tolerability of ACP-103 in the Treatment of Psychosis 
in Parkinson's Disease 
Version Date of Amendment 1: 
05 August, 2014 
I have read and approve the statistical analysis plan for the study listed above. 
Director, Biostatistics & SAS Programming 
Date 
VP, Regulatory Affairs & Development 
Date 
EVP, Development & CMO 
Date 


ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 5 
DEFINITIONS ................................................................................................................. 7 
0 
REVISION HISTORY ................................................................................. 10 
1 
INTRODUCTION ........................................................................................ 10 
2 
STUDY OVERVIEW ................................................................................... 10 
2.1 
General Study Design and Plan .............................................................. 10 
2.2 
Study Procedures (Based on Protocol Amendment 6) ......................... 11 
2.3 
Randomization and Blinding ................................................................... 12 
2.4 
Sample Size Estimation ........................................................................... 12 
3 
STUDY OBJECTIVE AND ASSESSMENTS ............................................. 12 
3.1 
Study Objective ........................................................................................ 12 
3.2 
Clinical Rating Scales .............................................................................. 12 
3.3 
Safety and Pharmacokinetic Endpoints ................................................. 12 
4 
ANALYSIS SETS ....................................................................................... 12 
5 
STATISTICAL CONSIDERATIONS ........................................................... 13 
5.1 
General Statistical Procedures................................................................ 13 
5.2 
Multiplicity Issues ..................................................................................... 13 
5.3 
Coding Dictionary ..................................................................................... 13 
5.4 
Analysis Visit Window, Time Periods and Missing Values ................... 13 
5.4.1 
Visit Windows for Clinical Rating Scales ............................................... 13 
5.4.2 
Summary Time Periods for Safety Results ............................................ 14 
5.4.3 
Missing Values.......................................................................................... 15 
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
5.5 
Subject Enrollment and Disposition ....................................................... 16 
5.6 
Core Study Information ............................................................................ 18 
5.7 
Study Drug Exposure and Overall Compliance ..................................... 18 
5.7.1 
Study Drug Exposure ............................................................................... 18 
5.8 
Important Protocol Deviations ................................................................ 19 
5.9 
Analysis of Demographic and Baseline Characteristics ....................... 19 
5.9.1 
Demographics and Baseline Characteristics ......................................... 19 
5.9.2 
Prior, Post and Concomitant Medications ............................................. 19 
5.9.3 
Medical History ......................................................................................... 20 
5.10 
Analysis of Pharmacokinetic Data .......................................................... 20 
5.11 
Analysis of Clinical Rating Scales .......................................................... 20 
5.11.1 
Scale for the Assessment of Positive Symptoms .................................. 20 
5.11.2 
Caregiver Burden Scale ........................................................................... 21 
5.11.3 
Clinical Global Impressions - Severity ................................................... 22 
5.11.4 
Clinical Global Impression – Improvement ............................................ 22 
5.11.5 
Resource Utilization in Dementia Scale – Lite ....................................... 22 
5.12 
Interim Analyses and Data Safety Monitoring Board ............................ 22 
5.13 
Analysis of Safety Data ............................................................................ 23 
5.13.1 
Adverse Events ......................................................................................... 23 
5.13.2 
Deaths and Other Serious and Significant Adverse Events ................. 24 
5.13.3 
Clinical Laboratory Data .......................................................................... 24 
5.13.4 
Vital Signs and Weight ............................................................................. 26 
5.13.4.1 
Vital Sign Parameters ............................................................................... 26 
5.13.4.2 
Orthostatic Hypotension ........................................................................... 26 
5.13.4.3 
Weight ........................................................................................................ 27 
5.13.5 
Electrocardiogram (ECG) ......................................................................... 27 
5.13.5.1 
ECG Parameters and Corrected QT (QTc) ............................................... 27 
5.13.5.2 
ECG Overall Interpretation ....................................................................... 28 
5.13.6 
UPDRS Parts II and III ............................................................................... 28 
5.13.7 
Non-Motor Symptom  Scale ..................................................................... 29 
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
5.13.8 
Physical Examination ............................................................................... 29 
5.14 
Additional Data Presentations................................................................. 29 
5.14.1 
Protocol Amendments ............................................................................. 29 
5.14.2 
Inclusion and Exclusion Criteria ............................................................. 29 
5.14.3 
Serum Pregnancy ..................................................................................... 30 
5.14.4 
Phone Contact .......................................................................................... 30 
6 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS ....................... 30 
7 
VALIDATION OF SAS® CODE .................................................................. 30 
REFERENCES .............................................................................................................. 31 
APPENDIX A:  SCHEDULE OF EVENTS .................................................................... 32 
APPENDIX B:  CRITERIA FOR MARKEDLY ABNORMAL LABORATORY VALUES 
IN SI (SYSTÈME INTERNATIONAL) UNITS ................................................................ 34 
 
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
LIST OF ABBREVIATIONS 
 
ACADIA 
ACADIA Pharmaceuticals Inc. 
AE(s) 
Adverse Event(s) 
ATC 
Anatomical/Therapeutic/Chemical 
BMI 
Body mass index 
BP 
Blood pressure 
CFB 
Change from Baseline 
CGI-I 
Clinical Global Impression – Improvement  
CGI-S 
Clinical Global Impression - Severity  
DBP 
Diastolic blood pressure 
EC 
Ethics Committee 
ECG(s) 
Electrocardiogram(s) 
eCRF 
Electronic case report form 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
ICF 
Informed Consent Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
msec 
millisecond(s) 
NDA 
New drug application 
NMSS 
Non-Motor Symptoms Scale 
PD 
Parkinson’s Disease 
PDP 
Parkinson’s Disease psychosis 
PE(s) 
Physical Examination(s) 
PK 
Pharmacokinetic 
PR 
PR interval on an electrocardiogram tracing 
QRS 
QRS interval of electrocardiogram 
QT 
QT interval of electrocardiogram 
QTc 
QT interval of electrocardiogram; corrected for heart rate 
QTcF 
Corrected QT interval by the method of Fridericia 
QTcB 
Corrected QT interval by the method of Bazett 
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
RUD-Lite 
Resource Utilization in Dementia Lite 
SAE(s) 
Serious Adverse Event(s) 
SAPS 
Scale for the Assessment of Positive Symptoms 
 
SAP-H+D 
Combined SAPS-Hallucinations and Delusions Score 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
TEAE 
Treatment-Emergent Adverse Event 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
US 
United States 
WHO 
World Health Organization 
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
DEFINITIONS 
The following definitions are developed for the purpose of statistical analysis and data 
tabulation. 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence or 
unintended change from the subject’s pre-treatment condition, 
including inter-current illness, that occurs during the course of a 
clinical trial after treatment has started, whether considered 
related to study treatment or not.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.   
Baseline 
Baseline is defined as the last available measurement taken prior 
to the first study drug administration in the ACP-103-015 study.  
If an ACP-103-015 baseline assessment was not scheduled to 
be performed, then the baseline value will be taken from the last 
available measurement in the core study. 
Change from 
Baseline 
For any given parameter at any given visit, the change from 
baseline (CFB) is defined as the parameter value for the given 
visit minus the Baseline value. 
Descriptive 
Statistics 
Number of subjects, mean, median, standard deviation, standard 
error of the mean, minimum and maximum for continuous 
measurements; number and percentage of subjects in each level 
of a categorical measurement. 
Safety Analysis 
Set 
The safety analysis set includes all enrolled subjects who receive 
any study drug in the ACP-103-015 study.   
Safety 
Assessments 
• Adverse events 
• Vital Signs   
• Clinical Laboratory Tests  
• Electrocardiogram (ECG) 
• Physical  Examinations 
Baseline  
Procedures 
Subjects enrolled within 1-week of completing the double-blind 
period a previous trial with pimavanserin are not required to 
undergo baseline procedures (except an update to the medical 
history and baseline RUD-Lite, Appendix A).  If they were 
enrolled after 1-week, all baseline procedures were required.   
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
Serious Adverse 
Event 
A serious adverse event (SAE) is any AE with any of the 
following outcomes:  
• Results in death; 
• Is life-threatening (i.e., the subject was at risk of death at 
the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more 
severe); 
• Requires inpatient hospitalization or prolongation of 
existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly or birth defect; 
• Is an important medical event that may not be immediately 
life-threatening or result in death or hospitalization but 
based on appropriate medical judgment may jeopardize 
the subject or may require medical or surgical intervention 
to prevent one of the outcomes listed above.  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. 
Scheduled Visit 
A scheduled visit is any planned visit per the protocol schedule of 
events. 
Study Day 1 
Study day 1 is defined as the date of first administration of study 
drug (pimavanserin) in the ACP-103-015 study. 
Study Day n 
Study day n represents a visit or assessment that occurs n days 
relative to the start of study drug in the ACP-103-015 study, 
computed as: (date of visit – study day 1) + 1 if the date of visit 
occurs on or after date of first dose; otherwise computed as: 
(date of visit – study day 1).  Note that there is no day 0. 
Study Duration 
The duration of the open-label use of pimavanserin will be 
determined based on clinical evaluations  but may continue for as 
long as this drug is considered to be well tolerated and 
efficacious, and until such time as pimavanserin is approved and 
commercially available 
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
Treatment-
Emergent Adverse 
Event 
A treatment-emergent adverse event (TEAE) is defined as an 
adverse event started between first study dose date and 30 days 
after the last dose date in the ACP-103-015 study. 
Treatment Group 
All subjects will receive 40 mg of pimavanserin once per day  
(QD). 
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
0 
REVISION HISTORY 
This statistical analysis plan is amended to reflect the following changes: 
•
Added imputation rules for missing or partial medication end dates.  See Section
5.4.3 for details.
•
Added summary of disposition by Sponsor re-classified withdrawal reasons.  See
Section 5.5 for details.
•
Concomitant medications are summarized by indication (motor function,
dementia, psychosis, or other).  See Section 5.9.2 for details.
•
Removed redundant categorical analysis of caregiver burden scale (CBS) data.
See Section 5.11.2 for CBS analysis.
•
The criteria for markedly abnormal laboratory values was revised to reflect SI
unit.  See Appendix B for details.
•
Various administrative text revisions to assure clarity.
1 
INTRODUCTION 
This statistical analysis plan covers the detailed procedures for performing statistical 
analyses and producing tables and listings in the study described in ACADIA 
Pharmaceuticals Inc. Protocol ACP-103-015 (Amendment 6, dated 30June2010). 
2 
STUDY OVERVIEW 
2.1 General Study Design and Plan 
This study will be conducted as a multi-center, open-label extension study.  Subjects 
who have completed blinded treatment in a previous study of pimavanserin in 
Parkinson’s Disease Psychosis (PDP), and who may, in the opinion of the Investigator, 
benefit from treatment with pimavanserin, will be enrolled in this extension study for 
safety evaluation.  All subjects were required to have a caregiver.  Subjects may be 
enrolled in ACP-103-015 as early as the last visit of the treatment phase of the prior 
blinded study OR up to 28 days following completion of this blinded treatment period. 
Subjects who enroll in ACP-103-015 within one week of completion of the treatment 
phase of the prior blinded study will not be required to complete a full baseline visit (Day 
1) (see Appendix A).
Subjects who are enrolled greater than one week following completion of the prior 
blinded study will be required to complete a full baseline evaluation for ACP-103-015. 
Once per day, subjects will be administered 40 mg of pimavanserin (two 20 mg tablets), 
orally, preferably in the morning.  Dose changes (increases or decreases) will NOT be 
allowed.     
All subjects will be required to visit the study site at Week 2, Month 1, Month 3, Month 6, 
Month 9, Month 12, and every six months thereafter (every 3 months before Protocol 
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    10    
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ACADIA Pharmaceuticals Inc.  
Statistical Analysis Plan (SAP) ACP-103-015 
Amendment 6) to complete safety and clinical evaluations.  Unscheduled clinical 
evaluations may occur at any time if deemed appropriate by the Investigator. 
2.2 Study Procedures (Based on Protocol Amendment 6) 
Before any subjects may be enrolled in the study, ACADIA and/or designee must obtain 
a copy of essential documents including the following: 
•
Institutional Review Board (IRB) or Ethics Committee (EC) approval of the
protocol;
•
IRB- or EC-approved Informed Consent Form (ICF);
•
Health Insurance Portability and Accountability Act (HIPAA) form (where
appropriate);
•
Other documents required by local regulations, as applicable.
Each subject must sign the approved ICF and, where appropriate, HIPAA forms prior to 
the administration of any measures required for this clinical study.  Each subject’s 
caregiver signed and dated an ICF.  Each subject who meets all eligibility criteria will be 
assigned a unique identification number.  No subject will be enrolled more than once in 
the study.  Once the identification number has been assigned to a subject, no attempt 
should be made to use that number again. 
The baseline day (Day 1) will represent the first day of the study and the first day of 
dosing with study drug in the ACP-103-015 study.  Baseline evaluations will be 
conducted on Day 1, prior to administration of the first dose of study drug on that day.  
All subjects will be dosed with 40 mg of pimavanserin administered orally, once per day. 
All subjects will be required to visit the study site at Week 2 (Day 14 ± 3 days), Month 1 
(Day 28 ± 3 days), Month 3 (Day 84 ± 7 days), Month 6 (Day 168 ± 7 days), Month 9 
(Day 252 ± 7 days), Month 12 (Day 336 ± 7 days), and every six months (every 168 
days ± 7 days) thereafter to complete safety and clinical evaluations.  (Note:  Prior to 
Amendment No. 6, 30 June 2010, subjects had study visits beyond Month 12 performed 
every 3 months).  Unscheduled clinical evaluations may occur at any time if deemed 
appropriate by the Investigator. If the subject terminates the study at any time other than 
a planned visit the subject will be required to visit the clinic for an end-of-study 
evaluation.   
Blood samples for determination of pimavanserin plasma concentration will be obtained 
prior to study drug administration at Week 2, Month 1, Month 2, Month 3, Month 6, 
Month 9, Month 12, and every 6 months thereafter, and at end-of-study, . 
Safety assessments (clinical safety laboratory tests, vital sign measurements, physical 
examinations, and electrocardiograms [ECGs]) will be conducted at scheduled times 
throughout the study.  Adverse events (AEs) and the use of concomitant medications 
will be monitored from the time of informed consent through the final visit.   
Appendix A displays the schedule of events and assessments. 
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2.3 Randomization and Blinding 
Not applicable. 
  
2.4 Sample Size Estimation 
Not applicable. 
 
3 
STUDY OBJECTIVE AND ASSESSMENTS 
3.1 Study Objective 
The objective of this study is to assess the long-term safety and tolerability of 
pimavanserin for the treatment of PDP. 
 
3.2 Clinical Rating Scales 
The Caregiver Burden Scale, Clinical Global Impression-Severity (CGI-S), Clinical 
Global Impression–Improvement (CGI-I), and Unified Parkinson’s Disease Rating Scale 
(UPDRS; a safety measure) parts II and III will be administered at all scheduled post-
baseline visits.  The Scale for the Assessment of Positive Symptoms (SAPS) will be 
administered at Month 1 only. 
The Non-Motor Symptom scale (NMSS; a safety measure) for PD was initially collected 
in this study but was discontinued with amendment 6.  Results will be presented in a 
data listing but will not be summarized. 
The Resource Utilization in Dementia (RUD)-Lite (health economics outcome measure) 
will be collected at baseline (all subjects had a baseline RUD-Lite performed), Month 
12, every 6 months thereafter, and at end of study. 
 
3.3 Safety and Pharmacokinetic Endpoints 
The safety and pharmacokinetic assessments include the following: 
• AEs; 
• Physical examinations (PEs); 
• Vital signs and body weight; 
• ECGs; 
• Clinical Laboratory including clinical chemistry, hematology, and urinalysis; 
• Pimavanserin plasma concentrations (trough). 
 
4 
ANALYSIS SETS  
All analyses will be performed on the safety analysis set, which is defined as: all 
enrolled subjects who receive at least one dose of study drug (pimavanserin). 
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Statistical Analysis Plan (SAP) ACP-103-015 
5 
STATISTICAL CONSIDERATIONS 
5.1 General Statistical Procedures 
Statistical summaries will be generated using SAS® software, version 9.3 or higher.  No 
formal statistical tests will be conducted.  Unless otherwise specified, continuous 
parameters will be summarized using the following descriptive statistics: number of 
observations, mean, median, standard deviation (SD), standard error of the mean 
(SEM), minimum and maximum.  Categorical parameters will be summarized using the 
number and percentage of subjects in each level of a category.   
Descriptive statistics will be presented using a significant figure rule: the minimum and 
maximum will have the same number of significant figures as the data; the mean and 
median will have one more significant figure than the data being summarized; the SD 
and SEM will have two more significant figures than the data being summarized; and 
the sample size (n) will be reported as an integer. 
Unless otherwise indicated, descriptive statistics will be reported for observed cases 
only and missing data will not be imputed.  Missing observations will not be taken into 
account when calculating frequencies, unless otherwise indicated.  By-visit summary 
tables will include all available subjects’ data up to 4 years (192 weeks) on study, and 
any data beyond that point will be summarized in a single visit (>192 weeks).  For 
laboratory, vitals, and ECGs by time period summaries an additional last assessment 
will be included. 
Data listings will include all data for all subjects.  Listings will present data sorted by site 
number, subject identification, study day, and visit (both nominal and derived, if 
applicable), unless otherwise specified.  If a listing includes a derived visit, then in those 
cases where a subject has more than one result in the derived visit window the result 
that is used for analysis will be flagged in the listing. 
 
5.2 Multiplicity Issues 
Multiplicity is not an issue because there are no formal statistical analyses. 
 
5.3 Coding Dictionary 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 15.1).  Prior and concomitant medicationswill be coded using the 
March 2013 version of the World Health Organization (WHO) Drug Dictionary. 
 
5.4 Analysis Visit Window, Time Periods and Missing Values 
5.4.1 Visit Windows for Clinical Rating Scales 
For clinical rating scales (e.g. SAPS associated scores, CGI associated scores and 
CBS) measured between first dose date and last dose date + 3, data will be 
summarized using the derived visit based on the visit windows shown in Table 1.  
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Statistical Analysis Plan (SAP) ACP-103-015 
Nominal visits as specified in Appendix A will be re-assigned to the derived visits.  The 
re-assigned visit will be referred to as the ‘derived visit’ as identified in Table 1 below.  
After reassignment of a visit, if there are multiple assessments for the same visit, the 
assessment nearest to the target study day will be kept for analysis.  In the event of a 
tie, the assessment from the earlier study day will be kept for analysis.  Unscheduled 
visits are included in the visit re-assignment.  
Table 1. Visit Assignments for Clinical Rating Scales Assessments 
Derived Visit 
Target Study 
Day* 
Time Interval 
(Study Day Range) 
Baseline (Day 1) 
1 
Last value on or before the first dose 
Week 2 
15 
2 – 21 
Week 4 
29 
22 – 42 
Week 12 
85 
43 – 126 
Week 24 
169 
127 – 210 
Week 36 
253 
211 – 294 
Week 48 
337 
295 – 421 
Week 72 
505 
422 – 589 
Week 96 
673 
590 – 757 
Week 120 
841 
758 – 925 
Week 144 
1009 
926 – 1093 
Week 168 
1177 
1094 – 1261 
Week 192 
1345 
1262 – 1429 
>Week 192 
1513 
1430 and up 
*Target study day is relative to date of first dose in the ACP-103-015 study.
The study day is defined as: 
For visits on or after the reference day: study day = visit day – reference day +1 
For visits before the reference day: study day = visit day – reference day where 
the reference day equals the start day of study drug in the ACP-103-015 study. 
5.4.2 Summary Time Periods for Safety Results 
For safety assessments (AEs, laboratory tests, vital signs, ECG data, UPDRS 
II+III and physical examinations), the data summary will be based on 
chronological time periods as defined in Table 2.  Rules for determining the 
analysis values within each time period are detailed in Section 5.13. 
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Table 2. Safety Summary Time Periods 
Time Period 
Study Day Range 
AE Onset 
Other Safety Measurement 
Baseline 
N / A 
Last value on or before the first dose 
First 4 weeks 
1* - 28 
2* - 28 
1 – 3 months 
29 – 91 
29 – 91 
>3 – 6 months 
92 – 183 
92 – 183 
>6 – 12 months  184 – 365 
184 – 365 
>1 – 2 years 
366 – 730 
366 – 730 
>2 – 3 years 
731 – 1095 
731 – 1095 
>3 – 4 years 
1096 – 1461 
1096 – 1461 
>4 years 
>= 1462 
>= 1462 
* Protocol procedures specified that all baseline assessments were to be done before 
administration of study drug on Day 1. For conservative reason, AEs started on Day 1 are 
considered “post-baseline”. 
   
5.4.3 Missing Values 
Unless otherwise specified, missing values will not be imputed for any of the rating 
scales or questionnaires.  A missing value is defined as one which is blank, not done, or 
not applicable on the eCRF.  If a scale has a “Not Assessed” response, then that value 
will be considered a missing value for analysis.  In addition, if one or more items in a 
given subscale is missing then the entire subscale will be set to missing.  In case a 
questionnaire consists of more than 1 subscale, any non-missing subscales will be used 
for analysis.  For example, if in the SAPS scale the Hallucination subscale has a 
missing item, but the Delusion subscale is complete, then the Delusion subscale will be 
analyzed per the analysis plan.  For the CGI-S and CGI-I questionnaires, a response of 
“Not assessed” will be treated as a missing value as well. 
For questionnaires that utilize a total score (NMSS, Caregiver Burden Scale), if any of 
the individual items that contribute to the total score are missing, the total score will also 
be set to missing. 
Missing baseline assessments will not be imputed. However, the SAPS and CGI-S 
scales were not collected at the ACP-103-015 baseline; therefore, the last core study 
assessment will serve as the ACP-103-015 baseline assessment for these scales. 
Missing dates for AEs and concomitant medications will be imputed for the purpose of 
establishing the time of event in relation to study treatment.  All data listings will display 
data as reported on the eCRF.  When AE onset date or concomitant medication dates 
are missing or incomplete, the study days (onset or start day relative to first dose date) 
will be calculated based on imputed value.   
The imputation rules for AE/concomitant medication start dates are as follows: 
• If a full date is missing, impute date as date of first dose (study day 1); 
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Statistical Analysis Plan (SAP) ACP-103-015 
• If the day component is missing from full date, date is imputed as study 
day 1 if the date is in the same month and year as first dose, otherwise 
impute as the 1st of the month; 
• If the month and day components are missing from full date, but year is 
present, the date is imputed as January 1 if the year is different than the 
year of first dose, or imputed as the first dose date if the year is the same 
as the year of first dose; 
• If any of the above imputations result in a start date which is later than an 
existing complete end date, the start date will be set equal to the end date. 
Missing end dates for AE will not be imputed. 
The imputation rules for concomitant medication end date are as follows: 
• If a full date is missing and the status of the medication is not ongoing, impute 
date as the last dose date; 
• If the day component is missing from full date, impute date as the last day of the 
month; 
• If the month and day components are missing from full date, but year is present, 
the date is imputed as last dose date if the year is the same as the last dose date 
and medication start date is prior to last dose date, otherwise impute as the last 
day of the year; 
• If any of the above imputations result in the medication end date which is prior to 
the medication start date, the medication end date will be set equal to the 
medication start date. 
 
For AE listing, AEs missing severity or relationship will be displayed as missing to reflect 
the raw data collected on eCRF.  For AE summary by severity, AEs with a missing 
severity will be tabulated as “severe”.  AEs with missing relationship will be tabulated as 
related. 
The last dose date is collected on the discharge eCRF.  If a subject has withdrawn from 
the study, but the last dose date is reported as a partial date, then the last dose date will 
be imputed using logical algorithms utilizing other reported data (e.g. death date if died, 
AE end date if discontinued due to AE, maximum projected dose date based on last 
dispensed and returned tablets, database snapshot date, …etc).  The complete 
programming algorithms are detailed in a separate programming specification 
document. 
 
5.5 Subject Enrollment and Disposition 
Subject enrollment by protocol amendments and subject counts by study center and 
prior study will be summarized. 
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Statistical Analysis Plan (SAP) ACP-103-015 
A summary of subject disposition will display the number of subjects enrolled, received 
study drug, and remained in the study (using visit dates recorded on the vital signs 
CRF) at the beginning of the following time periods: first 4 weeks (Study Days 1 to 28), 
1 to 3 months (Study Days 29 to 91), >3 to 6 months (Study Days 92 to 183), >6 month 
to 1 year (Study Days 184 to 365), >1 to 2 years (Study Days 366 to 730), >2 to 3 years 
(Study Days 731 to 1095), >3 to 4 years (Study Days 1096 to 1461) and >4 years 
(Study Days >=1462).  Also included in this summary will be subject discontinuations 
showing the number of subjects who terminated from the study according to the reason 
for study termination/discontinuation (Investigator reported and Sponsor re-classified).  
Reasons for study termination will also be summarized by the time period specified 
above. 
The withdrawal reasons as reported by the investigators on the eCRF are:  
• Adverse event 
• Death 
• Disease progression 
• Subject’s voluntary withdrawal of consent (Voluntary withdrawal of consent)  
• The Investigator determines that continuation in the study would be detrimental 
to a subject’s well-being because of development of a serious illness, any other 
significant change in clinical status, or any other compelling medical reason 
(Investigator decision) 
• Subject fails to comply with protocol requirements (Subject non-compliance) 
• Lost to follow-up 
• At discretion of Sponsor (Sponsor decision) 
 
To better understand the discontinuation pattern, ACADIA reviewed the withdrawal 
reasons and in some cases, on the basis of verbatim comments in the eCRF, re-
classified the reasons for discontinuation using the following categories: 
• Adverse event 
• Death 
• Lack of efficacy / PDP progression 
• PD /Concomitant disease progression 
• Voluntary withdrawal of consent  
• PDP improvement 
• Investigator decision 
• Subject non-compliance 
• Lost to follow-up 
• Sponsor decision 
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Statistical Analysis Plan (SAP) ACP-103-015 
Subject disposition and study completion by Investigator-specified and Sponsor-
reclassified reasons for termination will be presented in data listings and summary 
tables.  Dispositions will also be summarized by 3 regions: North America (US and 
Canada), Europe and India. 
  
5.6 Core Study Information 
The core (preceding) study information (studies ACP-103-012, ACP-103-014, and ACP-
103-020) will be summarized by protocol and will also be presented in a data listing. 
 
5.7 Study Drug Exposure and Overall Compliance 
5.7.1  Study Drug Exposure 
For the final CSR, all subjects’ study drug (pimavanserin) exposure will be calculated as 
last dose date minus first dose date + 1.  For the interim report(s), the drug exposure 
will be censored at the database snapshot date for the on-going subjects.  For example, 
if a subject had withdrawn from the study before the database snapshot, then the 
exposure duration for this subject is last dose date minus first dose date + 1; if a subject 
was still ongoing at the database snapshot date, then the exposure duration for this 
subject is database snapshot date minus first dose date + 1.   
A summary of study drug exposure will include the duration of exposure as a continuous 
measure in days and a categorical measure for the intervals (1-28 days, 29-91 days, 
92-183 days, 184-365 days, 366-730 days, 731-1095 days, 1096-1461 days, ≥1462 
days).  Total amount of administered pimavanserin (mg) will be estimated by (duration 
of exposure*40 mg).  Study drug exposure by Sponsor re-classified termination reasons 
will also be summarized.  Study drug exposure for subjects who died will also be 
summarized. 
Study drug exposure measures as described above will be presented in a listing. 
Since this is an open-ending study, time on pimavanserin treatment (time on study) will 
be evaluated for all subjects and by subgroups: baseline age group (≤75 years old or 
>75 years old), gender (female or male), and geographic area (North America or outside 
North America).  For subjects who have discontinued from study, the days on 
pimavanserin treatment in study -015 (not counting the exposure duration from the 
preceding study) will be calculated as last dose date minus first dose date + 1; 
otherwise the time on study will be censored at database snapshot date and will be 
calculated as database snapshot date minus first dose date + 1.  Kaplan-Meier 
estimates of percent subjects on treatment at 6 months (183 days), 1 year (365 days), 
1.5 years (548 days), 2 years (730 days), 2.5 years (913 days), 3 years (1095 days), 3.5 
years (1278 days) and 4 years (1461 days), as well as median days on treatment will be 
presented. 
In addition, Kaplan-Meier estimates percent subjects free of AEs leading to study 
termination or drug withdrawal and median days to due to AEs leading to study 
termination or drug withdrawal will be summarized for all subjects and by 
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Statistical Analysis Plan (SAP) ACP-103-015 
aforementioned subgroups.  For this analysis, if a subject has an AE leading to study 
termination or drug withdrawal, the time to event will be calculated as last dose date 
minus first dose date + 1; otherwise the time to event will be censored at either last 
dose date (for subjects who discontinued due to reasons other than AE) or database 
snapshot date (for ongoing subjects).  
 
5.8 Important Protocol Deviations 
Protocol deviation logs will be reviewed and the deviations will be categorized by 
deviation type and grouped as major or minor. 
A summary of the number and percentage of subjects with major deviations by 
deviation category will be provided.  A listing of major protocol deviations by site and 
subject will also be provided. 
  
5.9 Analysis of Demographic and Baseline Characteristics 
5.9.1 Demographics and Baseline Characteristics 
Demographic data (age at 015 first dose date, sex, and race) will be summarized for all 
subjects for the safety analysis set using descriptive statistics.  Summary of age 
categories (<65, 65-75, and >75 years) will also be presented.  Race/ethnicity will be 
presented as White, Black, Asian and other.  Region will be presented as North America 
(US and Canada), Europe, and India.  In addition, subject counts from 2 geographic 
areas, North America and outside North America (Europe and India combined) will also 
be presented since the number of subjects (N=18) in India was too small to make 
meaningful comparisons.  The geographic areas will be used for summarizing the 
clinical rating scales (Section 5.11) or mortality (Section 5.13.2).  
Demographic information as described above, along with childbearing status, method of 
birth control for subjects of childbearing potential, and date of birth will also be 
presented in a data listing. 
Baseline characteristics will include weight (kg), height (cm), BMI (kg/m2), and 
questionnaire scores for SAPS-PD, SAPS-H+D, SAPS-H, SAPS-D, UPDRS II+III, 
UPDRS II, and UPDRS III.  These parameters will be summarized with descriptive 
statistics.  For the questionnaire scores the last value from the core study will serve as 
the baseline value of the current study.  Each of these parameters will also be 
presented in a data listing. 
 
5.9.2 Prior, Post and Concomitant Medications 
Medications started prior to the day of the first dose of open-label study medication and 
continued into the study, or medications started on or after the day of the first dose of 
study medication and before or on the day of the last dose of the study medication will 
be reported as concomitant medications.  Medications stopped before the first date of 
study medication dosing will be considered prior medications.  Medications started after 
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Statistical Analysis Plan (SAP) ACP-103-015 
the day of last dose of study mediation will be considered post-treatment.  Prior, 
concomitant and post-treatment medications will be listed. 
The number and percentage of subjects using concomitant medications in each WHO 
Drug Anatomical/Therapeutic/Chemical (ATC) Level 3 (i.e., pharmacological subgroup) 
category and preferred term will be summarized.  Separate summaries will be 
presented for  
• Anti-psychotic medications 
• Medications indicated for dementia 
• Medications indicated for motor function 
• Medications not included in the preceding 3 categories. 
 
Number of concomitant medications will be summarized at first dose date and last dose 
date for overall, indicated for motor functions, dementia and antipsychotics.  
Antipsychotics taken post-treatment (medication started after the last dose date) will 
also be summarized. Multiple medications for the same subject may be classified to the 
same ATC level or preferred name.  However, subjects will only be counted once for 
each level of classification.   
Prior, concomitant, and post-treatment medications with the verbatim, ATC level 3 
category, preferred term, indication, dosage, route, unit, frequency, and start/stop dates 
of administration will be provided in a listing. 
  
5.9.3 Medical History 
A listing of the body system, verbatim condition/abnormality/procedure, date of onset, 
and an indicator for whether or not the condition is still present at baseline will be 
provided.  A summary table will also be provided. 
 
5.10 Analysis of Pharmacokinetic Data 
For the final clinical study report, pimavanserin plasma concentration data will be listed 
by subject with derived visit, most recent pimavanserin dose date and time, and PK 
sample collection date and time.  No summary table will be generated. 
 
5.11 Analysis of Clinical Rating Scales 
5.11.1 Scale for the Assessment of Positive Symptoms 
The Scale for the Assessment of Positive Symptoms (SAPS) was designed to measure 
positive psychotic symptoms.  Positive symptoms include delusions, hallucinations, 
abnormalities in language and behavior, and disordered thought processes.  Two of the 
SAPS subscales, Hallucinations and Delusions, will be administered in this trial as a 20-
item assessment.  The SAPS Hallucinations scale contains 7 items and the Delusions 
scale contains 13 items. The score for each item ranges from 0 to 5 (0 = absent, 1 = 
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Statistical Analysis Plan (SAP) ACP-103-015 
questionable, 2 = mild, 3 = moderate, 4 = marked, 5 = severe).  The last item of each 
scale is the “Global rating of severity” for the corresponding domain.  The combined 
score for SAPS-H+D will be derived as the sum of the 20 items, including the global 
ratings.  Possible scores range from 0 to 100.  If one or more of the 20 items is missing, 
the combined score is considered as missing at the visit.  The SAPS questionnaire will 
be administered at the Month 1 (Week 4) visit only.  Note that the baseline SAPS scores 
were measured at the end of preceding study. 
Nine of these 20 items from the SAPS Hallucinations and Delusions domains were 
found to be more prevalent in PDP subjects with more severe symptoms and therefore 
these items are expected to have improved clinical relevance and face validity.  This 
PD-adapted version of the SAPS (SAPS-PD; Voss et al., 2013) includes these 9 items: 
• H1 Auditory Hallucinations; 
• H3 Voices Conversing; 
• H4 Somatic or Tactile Hallucinations; 
• H6 Visual Hallucinations; 
• H7 Global Rating of Severity of Hallucinations; 
• D1 Persecutory Delusions; 
• D2 Delusions of Jealousy; 
• D7 Ideas and Delusions of Reference; 
• D13 Global Rating of Severity of Delusions. 
The SAPS-PD (9-item sum score), SAPS-H+D (20-item sum score), SAPS-H 
(hallucination subscale sum score), and SAPS-D (delusion subscale sum score) data 
will be summarized for all subjects and by geographic area (North America or outside 
North America) and by prior treatment (placebo, pimavanserin 10 mg, pimavanserin 20 
mg, or pimavanserin 40 mg).  Within North America, the SAPS-PD data will also 
summarized by prior treatment. 
The GSAPS-H+D (sum score of global rating of hallucination severity and global rating 
of delusion severity), GSAPS-H (global rating of hallucination severity), and GSAPS-D 
(global rating of delusion severity) data will be summarized for overall subjects. 
The SAPS-PD, SAPS-H+D, SAPS-H, SAPS-D, GSAPS-H+D, GSAPS-H, GSAPS-D, 
and SAPS individual item scores will be presented in listings. 
 
5.11.2 Caregiver Burden Scale 
The Caregiver Burden Scale (CBS) is a 22-item questionnaire completed by the 
subject’s caregiver.  Each item is rated on a scale of 0 - 4 where 0 = never, 1 = rarely, 2 
= sometimes, 3 = frequently, 4 = nearly always.  The total score of the Caregiver Burden 
Scale will be derived as the sum of the 22 items, with a possible range of 0 to 88.  The 
total score and change from baseline will be summarized by visit.  The data will also be 
summarized within each geographic area (North America and outside North America). 
 
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Statistical Analysis Plan (SAP) ACP-103-015 
5.11.3 Clinical Global Impressions - Severity 
The CGI-Severity (CGI-S) is a single-item score from a 7-point rating scale used to 
assess the investigator's global impression of severity of psychosis as it relates to this 
study population.  Scores range from 1 (Normal, not at all ill) to 7 (Among the most 
extremely ill patients).  Scores of 0 indicate 'Not Assessed' and will be converted to 
missing.  The CGI-S will be performed at each post-baseline study visit. 
The observed values of CGI-S will be summarized for each study visit.  The data were 
also summarized within each geographic area (North America and outside North 
America). 
 
5.11.4 Clinical Global Impression – Improvement 
CGI-Improvement (CGI-I) is a single-item score from a 7-point rating scale assessed 
only at post-baseline visits and is used to assess the improvement in subjects’ overall 
psychotic condition.  The 7-point scale ranges from 1 (Very much improved) to 7 (Very 
much worse).  Scores of 0 indicate ‘Not Assessed’ and will be converted to missing. 
The observed values for Clinical Global Impression of Improvement (CGI-I) will be 
summarized by visit.  Additionally the proportion of CGI-I responders [with responder 
defined as a subject with a score of 1 (very much improved) or 2 (much improved)] will 
be summarized by visit.  A CGI-I rating of 1 (very much improved) or 2 (much improved) 
represents the point at which clinically meaningful improvement in psychotic symptoms 
would be expected. 
The observed mean values and the CGI-I responders data will also be summarized 
within each geographic area (North America and outside North America). 
 
5.11.5 Resource Utilization in Dementia Scale – Lite 
RUD-Lite, a health economics measure, will be collected at baseline, Month 12 and 
every 6 months thereafter.  The individual item scores will be presented in a data listing.  
Additional analyses may be conducted and reported separately. 
 
5.12 Interim Analyses and Data Safety Monitoring Board 
To provide an adequate update of the long-term safety profile for pimavanserin’s new 
drug application (NDA) submission, a data snapshot was taken on 13DEC2013 and an 
interim analysis will be performed.   
There is no Data Safety Monitoring Board (DSMB) for this study.  Safety data are 
monitored throughout the study and aggregate safety reports are produced and 
reviewed approximately quarterly. 
   
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Statistical Analysis Plan (SAP) ACP-103-015 
5.13 Analysis of Safety Data 
All safety data summaries will be based on the safety analysis set. 
 
5.13.1 Adverse Events 
AEs started between first study dose date and 30 days after the last dose date will be 
considered treatment-emergent AE (TEAEs).  Any AEs with a completely missing start 
date will be considered as TEAEs.  All AEs and TEAEs will be summarized.  In addition, 
the number of TEAEs, and the number and percent of unique subjects with TEAEs will 
be summarized by system organ class (SOC) and preferred terms.  For SAEs, the SAE 
onset date will be used in place of the AE onset date for the determination of treatment-
emergent status and for assignment of the event to time windows and onset age 
groups. 
AEs will be summarized in terms of the proportion of subjects as well as number of 
events.  When calculating the proportion of subjects with AEs by time period or age 
groupeach subject will be counted in the numerator at most once and any repetitions 
will be ignored; the denominator will consist of all safety-evaluable subjects in the 
specified time period or age group.  When calculating the number of events, each 
unique record in the database will be counted once.  
Additional summaries of TEAEs will also be tabulated with respect to severity (mild, 
moderate, severe) and AEs of special interest.  Tabulations will also be provided for 
AEs by maximum severity where a subject with more than one event coded to the same 
preferred term will be classified according to the most severe event.  Similarly, in the 
tabulation by strongest relationship, a subject will be classified according to the event 
with the strongest relationship to study drug. 
An overall summary of all AEs and TEAEs will be presented.  The number and percent 
of unique subjects with TEAEs will be summarized by system organ class (SOC) and 
preferred term.  The number and percent of unique subjects with TEAEs that are 
determined by investigators as related (possibly, probably, or definitely) to study drug 
will also be summarized by SOC and preferred term.  Additional summaries of TEAEs 
will also be tabulated with respect to severity (mild, moderate, or severe), where a 
subject with more than one event coded to the same preferred term will be classified 
according to the more severe event.  A summary of TEAEs in descending order of 
frequency by preferred term will also be tabulated.  Listings of deaths, serious AEs and 
AEs leading to study treatment discontinuation will also be provided. 
The tabulation of TEAEs will be grouped by (1) time period at AE onset and (2) age at 
AE onset. 
(1) AEs grouped by time period at AE onset: For all TEAEs, serious TEAEs, TEAEs 
leading to discontinuation of study drug, and TEAEs of special interest (those 
that may be expected on the basis of pimavanserin’s pharmacology, those of 
special regulatory interest [suicidality, abuse liability etc], and those commonly 
associated with current antipsychotics), the count and percentage of subjects will 
be summarized by time period defined in Section 5.4.2 Table 2.  The 
denominator for a time period will be the number of subjects on treatment 
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Statistical Analysis Plan (SAP) ACP-103-015 
(including a 30-day follow-up) during that particular time period. TEAEs with fatal 
outcome will be summarized by time period at death. 
(2) AEs by age group at AE onset: For all TEAEs, serious TEAEs, TEAEs leading to 
discontinuation of treatment, and TEAEs of special interest, the count and 
percentage of subjects will be summarized by age category at the time of AE 
onset.  Age at onset will be categorized as follows: ≤ 50 years, 51 - 60 years, 61 
– 70 years, 71 – 80 years and 81 - 90 years.  The denominator for an age group 
will be the number of subjects on treatment (including a 30-day follow-up) while 
in that particular age group. TEAEs with fatal outcome will be summarized by age 
group at death. 
An AE listing by subject will display all events and will include the verbatim term in 
addition to the MedDRA SOC and preferred term.  This listing will also include all 
relevant CRF data associated with the event: date of onset , date of last dose, severity,  
outcome, relationship to study drug, action taken, and seriousness. 
In addition, AE tables also will be summarized by age group and onset time period for 
subject with concomitant antipsychotic use and without antipsychotic use. 
     
5.13.2 Deaths and Other Serious and Significant Adverse Events 
Treatment-emergent SAEs, TEAEs leading to discontinuation from the study or study 
drug, and TEAEs with fatal outcome will be summarized by time period as given in 
Table 2 in frequency tables by SOC and preferred term.  In addition, the overall AE 
summary table will also be presented for all events (i.e. treatment-emergent plus non-
treatment-emergent events).   
Subject listings of SAEs, deaths, and AEs leading to discontinuation of study drug will 
be provided.  These listings will provide all relevant eCRF data for each event including 
the date/study day of onset, date/study day resolved, date of last dose/study day of last 
dose, severity, outcome, relationship to study drug, action taken, and seriousness. 
Kaplan-Meier estimates of percent surviving subjects at 6 months, 1 year, 1.5 years, 2 
years, 2.5 years, 3 years, 3.5 years and 4 years, as well as median survival time will be 
computed for all subjects and by subgroups: baseline age group (≤75 years old or >75 
years old), gender (female or male), and geographic area (North America or outside 
North America).  If a subject is deceased, the survival time will be calculated as death 
date minus first dose date + 1; otherwise the survival time will be censored at the last 
dose date (for subjects who have discontinued from the study) or database snapshot 
date (for ongoing subjects).  
  
5.13.3 Clinical Laboratory Data 
Observed clinical laboratory data and change from baseline values will be summarized 
by time period for hematology, chemistry and numeric urinalysis using the periods 
specified in Section 5.4.2 Table 2.  For each laboratory parameter collected for each 
subject, within each time period, 2 different representations will be used for generating 
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Statistical Analysis Plan (SAP) ACP-103-015 
the population summary statistics: the highest and lowest measurement from that 
subject during that particular time period.  The highest or lowest measurement will 
capture the worst or the most extreme observed value (depending on the laboratory 
test, the highest or lowest or both can be concerning).  In addition to each time period, 
for each laboratory parameter, the last, highest and lowest measurement collected for 
each subject during the entire study period will also be summarized.   
For a subset of clinical laboratory parameters (red blood cell count, hemoglobin, white 
blood cell count, neutrophils, alkaline phosphatase, alanine aminotransferase , 
aspartate aminotransferase , bilirubin (total), gamma-glutamyl transferase, creatine 
phosphokinase, lactate dehydrogenase, blood urea nitrogen, creatinine, and uric acid) 
low [L], normal [N] or high [H] status will be determined based on the normal ranges 
provided by the testing laboratory.   
The count and percentage of subjects with markedly abnormal post-baseline clinical 
laboratory parameters tabulated for all subjects and a subset of subjects with normal 
baseline will also be presented by time period and overall as defined in Table 2 and for 
overall study period.  The criteria for markedly abnormal laboratory values are provided 
in Appendix B.  For each laboratory parameter, within each specified time period and for 
overall study period, if a subject has at least 1 measurement meeting the marked 
abnormal criterion, this subject will be counted as having an incidence.  The 
denominator for each laboratory parameter within each specified time period will be the 
total number of subjects with baseline and at least 1 post-baseline value within that 
particular time period.   
Clinical laboratory data will be displayed in data listings with date and study day of 
collection.  All units will be displayed according to the Système International (SI) 
conventions for units.  Out-of-range values will be flagged in the data listings (i.e., ‘L’ or 
‘H’). 
The routine laboratory panel includes: 
Hematology 
Complete blood count including White Blood Cell Count, Complete Differential (Relative 
and Absolute), Hematocrit, Hemoglobin, Red Blood Cell Count, Platelets, and 
Reticulocyte Count. 
Clinical Chemistry 
Sodium, Potassium, Chloride, Phosphorus , Calcium, Carbon dioxide, Blood urea 
nitrogen, Creatinine, Uric acid, Alanine Aminotransferase, Aspartate Aminotransferase, 
Gamma-Glutamyl Transferase, Alkaline Phosphatase, Total Bilirubin, Lactate 
Dehydrogenase, Albumin, Total Protein, and Creatine Kinase/Creatine Phosphokinase. 
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Statistical Analysis Plan (SAP) ACP-103-015 
Urinalysis 
Blood, Red Blood Cells, White Blood Cells, Protein, Glucose, Ketones, Specific Gravity, 
and pH (only the pH and specific gravity information was presented in the summary 
table; all urinarlysis data was presented in a listing) 
 
5.13.4 Vital Signs and Weight 
5.13.4.1 
Vital Sign Parameters 
Vital signs are collected at every study visit.  A summary of observed values and 
change from baseline by time period will be presented for orthostatic blood pressure 
(systolic and diastolic in mmHg) and pulse (beats per minute), measured supine (after 5 
minute), and standing (after 1 minute), respiratory rate, oral temperature and weight.  
For each vital sign parameter collected for each subject, within each time period, 2 
different representations will be used for generating the population summary statistics: 
the highest and lowest measurement.  The highest or lowest measurement will capture 
the worst or the most extreme observed value.  In addition to each time period, for each 
vital sign parameter, the last, highest and lowest measurement collected for each 
subject during the entire study period will also be summarized. 
All observed and change from baseline vital sign values will be provided in a listing with 
date of collection, study day, and time period. 
 
5.13.4.2 
Orthostatic Hypotension 
Orthostatic hypotension is assessed each time vital signs are collected for pulse and 
blood pressure through the comparison of 5 minute supine results against 1 minute 
standing.  The count and percentage of subjects experienced orthostatic hypotension as 
defined below will be summarized for each time period defined in Section 5.4.2 Table 2 
and for overall study period (at any timepoint postdose) for subjects for whom 
orthostatic hypotension was not present at baseline.  If a subject has at least 1 
measurement meeting the orthostatic hypotension criteria during a given time period, 
this subject will be counted as having an incidence for that time period.  The 
denominator for percentages is the number of subjects with non-missing data at each 
visit. 
Orthostatic hypotension occurs if:  
• there is a decrease of ≥20 mmHg in systolic blood pressure (SBP) 
OR 
• there is a decrease of ≥15 mmHg in diastolic blood pressure (DBP) 
OR 
• there is an increase of ≥20 bpm  in pulse rate (PR);  
each measured from 5 minutes supine to 1 minute standing at the same visit. 
An overall count and percentage of subjects experienced orthostatic hypotension based 
on findings from either AE records (i.e. where the preferred term = ‘Orthostatic 
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Statistical Analysis Plan (SAP) ACP-103-015 
hypotension’) or vital signs (orthostatic changes in blood pressure and pulse) will also 
be presented.  Data listing of blood pressure and pulse measurements for these 
subjects will also be presented. 
   
5.13.4.3 
Weight 
Body mass index (BMI) is calculated from height and weight recorded at each visit.  
Observed values in weight (kg) and BMI (kg/m2) will be summarized with descriptive 
statistics by time period as defined in Section 5.4.2 Table 2.  Within each time period: 
the highest and lowest measurement from each subject will be summarized.  In addition 
to each time period, the last, highest and lowest measurement collected for each 
subject during the entire study period will also be summarized.  
In addition, a summary table of clinically meaningful weight change will be provided by 
time period and overall (any timepoint postdose).  Two criteria will be applied and 
tabulated separately: (1) weight increase or decrease > 7% from baseline; or (2) a BMI 
<19 or >32 kg/m2.  Within each time period if a subject has at least 1 measurement 
meeting the criterion, this subject will be counted as having the incidence for that time 
period.  The denominator for percentages is the number of subjects with non-missing 
data within each time period. 
All observed values for height, weight, and BMI will be provided in a listing with date of 
collection, study day, and time period.  Subjects with a clinically meaningful weight 
change from baseline will be identified. 
   
5.13.5 Electrocardiogram (ECG) 
5.13.5.1 
ECG Parameters and Corrected QT (QTc) 
Observed and change from Baseline values for each time period as defined in Section 
5.4.2 Table 2 will be summarized with descriptive statistics for QT, corrected QT (QTcF 
and QTcB), heart rate, PR Interval, R-R Interval, and QRS Interval.  If a subject did not 
have a baseline ECG assessment, then the last available ECG from the core study will 
be used as the ACP-103-015 baseline value.  For each ECG parameter collected for 
each subject, within each time period, 2 different representations will be used for 
generating the population summary statistics: the highest and lowest measurement.  
The highest or lowest measurement will capture the worst or most extreme observed 
value.  In addition to each time period, for each ECG parameter, the last, highest and 
lowest measurement collected for each subject during the entire study period will also 
be summarized.  In addition, ECG parameters will also be summarized from pre-PIM 
baseline and change from pre-PIM baseline.  The definition of pre-PIM baseline is: for 
subjects who received pimavanserin in prior studies, baseline value is obtained from 
prior-study baseline (pre-exposure); for all other subjects, study -015 baseline is used.  
Bazett’s corrected QT will be calculated using the formula QTcB = QT/ √𝑅𝑅
2
.  
Fridericia’s corrected QT will be calculated using the formula QTcF = QT/ √𝑅𝑅
3
.   
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Statistical Analysis Plan (SAP) ACP-103-015 
An additional summary of the proportion of subjects with values of normal or 
abnormalfor each parameter and time period as described above will be provided.  
Table 3 below lists ECG parameter normal ranges.  The proportion of subjects with 
treatment-emergent abnormally high or abnormally low values will also be presented by 
time period and overall (at any timepoint postdose).  
Table 3. ECG Parameter Normal Ranges 
 
 
 
 
 
 
The proportion of subjects with QTcF ≤ 450 msec, 451 - ≤ 480 msec, 481 - ≤ 500 msec 
and > 500 msec, and QTcF change from Baseline <10 msec, 10 - 29, 30 - 59 msec, and 
≥ 60 msec will be summarized by time period and overall (at any timepoint postdose).  
For each ECG parameter, within each specified time period, if a subject has multiple 
results, the worst (longest interval) measurement within the time period will be used as 
the analysis value. 
All summaries will also be performed in subgroups by gender.   
Listings of the ECG parameters, including QTcB, as described above will include date 
and time of collection, observed values, and flag indicators for any value outside of the 
normal range (L for below normal, H for above normal).  
    
5.13.5.2 
ECG Overall Interpretation 
The ECG interpretation (normal, abnormal not clinically significant [NCS], abnormal 
clinically significant [CS]) will be summarized for each time period and overall.    Within 
each time period if a subject has at least 1 clinically significantly abnormal record, this 
subject will be counted as having the incidence for that time period.  The ECG 
parameters for these subjects will be presented in a data listing. 
The ECG interpretation will also be provided in a listing with date and time of collection 
and additional comments. 
 
5.13.6 UPDRS Parts II and III 
The Parts II+III UPDRS score will be derived as the sum of the 40 items from activities 
of daily living (Part II, 13 items) and motor examination (Part III, 27 items), with a range 
of 0 to 160 (for each item the score ranges from 0 (normal or absent of symptom) to 4 
(worst condition)). 
ECG Parameter (unit) 
Normal Range 
QRS Interval (msec) 
60 – 100 
QTcF (msec) 
<500 
QTcB (msec) 
<500 
QT Interval (msec) 
360 – 470 
PR Interval (msec) 
120 – 200 
R-R Interval (msec) 
550-1500 
Heart Rate (beats per min) 
40 – 110 
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Statistical Analysis Plan (SAP) ACP-103-015 
For UPDRS Parts II+III, Part II, and Part III scores, the highest (worst) measurement will 
be used for generating the population summary statistics within each time period.  In 
addition, for the overall study period, the last and the highest  measurement from each 
subject will be summarized. 
 
5.13.7 Non-Motor Symptom  Scale 
The Non-motor Symptoms Scale (NMSS) is a 32 item scale that measures non-motor 
symptoms of PD.  NMSS contains nine domains: cardiovascular including falls (2 
items), sleep/fatigue (5 items), mood/cognition (7 items), perceptual 
problems/hallucinations (3 items), attention/memory (3 items), gastrointestinal tract (3 
items), urinary (3 items), sexual function (2 items), and miscellaneous (4 items). Each 
item has a severity rating (0 to 3) and a frequency rating (1 to 4).  The score for each 
item is the product of severity and frequency with a range or 0 to 12.  NMSS total score 
is the sum of the 32 item scores, ranging from 0 to 384.  
The NMSS individual item scores, along with the total score, will be presented in a data 
listing by domain.  The NMSS was initially collected during this study, but was 
discontinued with Amendment No. 6. 
   
5.13.8 Physical Examination 
Physical examination results (normal, abnormal) will be summarized in a frequency 
table by body system by time period.   
Data listings will include date and time of evaluation, any abnormal findings within each 
body system, clinical significance, and a comment describing the abnormality and 
clinical significance of the abnormality. 
 
5.14 Additional Data Presentations 
5.14.1 Protocol Amendments 
Study enrollment started with the original Protocol.  The number and percent of subjects 
who consented to the original Protocol, Amendment 1, Amendment 2, Amendment 3, 
Amendment 4, Amendment 5, Amendment 6, and any potential future Amendments of 
the protocol will be summarized in a table.   
Subjects’ consent to protocol amendments will also be presented in a data listing. 
 
5.14.2 Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria will be provided in separate data listings, ordered by 
protocol amendment.  Violations of inclusion and exclusion will be listed by protocol 
amendment and subject.  Waivers to the inclusion and exclusion criteria will be listed by 
site and subject. 
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Statistical Analysis Plan (SAP) ACP-103-015 
   
5.14.3 Serum Pregnancy 
Pregnancy tests (females only) are performed on serum with results recorded in the 
eCRF.  A listing of all qualitative pregnancy test results (positive, negative) will be 
provided with date and study day of collection. 
 
5.14.4 Phone Contact 
Documentation of phone contact with the subject to assess tolerability, as reported on 
the eCRF, will be presented in a data listing along with reason for no contact, if 
applicable. 
 
6 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS 
Section 10.1 of the Protocol specified that all analyses would be performed SAS using 
version 8.  However, SAS version 9.3 (or higher) will be used for all statistical 
analyses. 
 
7 
VALIDATION OF SAS® CODE 
All SAS programs used in the production of statistical analyses, analysis datasets, 
tables, listings, and figures will be validated by independent programming prior to 
finalization or with a peer review of the SAS log files.  In addition, all program output 
will be independently reviewed.  The validation process will be used to confirm that 
statistically valid methods were implemented and that all data manipulations and 
calculations were accurately performed. 
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Statistical Analysis Plan (SAP) ACP-103-015 
REFERENCES 
ACP-103-015 Clinical Study Protocol Amendment 6, Acadia 
Pharmaceuticals Inc. 30 June 2010. 
ICH Guidance E3 – Structure and Content of Clinical Study Reports. 
Voss T, et al. (2013), Performance of a shortened Scale for Assessment of 
Positive Symptoms for Parkinson’s disease psychosis, Parkinsonism and 
Related Disorders 19(3), 295-9. 
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Statistical Analysis Plan (SAP) ACP-103-015 
APPENDIX A:  Schedule of Events 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Baseline
1
(Day 1) 
 Week 2 
Day 14    
± 3 days 
 Month 1 
Day 28    
± 3 days 
Month 3 
Day 84 
+ 7days 
Month 6 
Day 168 
+ 7days 
Month 9 
Day 252 
+ 7days 
Month 12 
(Day 336 ± 7 days) 
AND 
every 6 months 
thereafter 
(168 days ± 7 
days) 
End-of-
Study 
(if subject 
withdraws 
or is 
terminated 
from the 
study) 
Informed Consent 
X 
Medical History 
X2
Inclusion/Exclusion 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam3 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Labs 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy 
Test 
X 
X 
X 
X 
X 
X 
Plasma PK Sample4 
X 
X 
X 
X 
X 
X 
X 
Caregiver Burden 
Scale 
X 
X 
X 
X 
X 
X 
X 
1 Subjects that enroll in this study within one week of completion from a previous blinded study of pimavanserin in will only be required to sign an informed consent form, complete 
an update to the medical history that was performed during the screening and baseline visit of the previous study, complete the Baseline RUD-Lite, and receive study drug during the 
baseline visit.  Subjects that enroll greater than one week of completion from the previous blinded study will be required to complete ALL baseline assessments.  All assessments are 
to be performed PRIOR to investigational drug administration. 
2 The medical history to be taken at baseline will be an update to the medical history taken during the screening and baseline visits of the previous study.  Any AEs that occur after the 
informed consent is signed and before the first dose of investigational drug is taken are to be recorded in the updated medical history and NOT in the AEs log.  
3 The physical examination performed on Week 2, Month 1, Month 3, Month 6, Month 9, Month 12 and every 6 months thereafter will be an update to the full physical examination 
conducted during either the last visit of the previous study or at Baseline of this study. 
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Statistical Analysis Plan (SAP) ACP-103-015 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Baseline 
(Day 1) 
 Week 2 
(Day 14 
± 3 days) 
 Month 1 
(Day 28 
± 3 days) 
Month 3 
Day 84 
+ 7days 
Month 6 
Day 168 
+ 7days 
Month 9 
Day 252 
+ 7days 
Month 12 
(Day 336 ± 7 days) 
AND 
every 6 months 
thereafter 
(168 days ± 7 
days) 
End-of-
Study 
(if subject 
withdraws 
or is 
terminated 
from the 
study) 
SAPS5 
 
 
X 
 
 
 
 
 
UPDRS Parts II & III6 
 
X 
X 
X 
X 
X 
X 
X 
CGI-S and CGI-I7 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events8 
X 
X 
X 
X 
X 
X 
X 
X 
RUD-Lite1, 9 
X 
 
 
 
 
 
X 
X 
Prior/Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Drug 
Administration10 
X 
X 
X 
X 
X 
X 
X 
 
4 Plasma samples for determination of pimavanserin levels are to be taken PRIOR to investigational drug administration on study days; on study visit days the subject should NOT 
take the day’s dose of investigational drug at home.  They should wait until they are at the clinical site. 
5 Scale for the Assessment of Positive Symptoms (SAPS) may be administered by a Central Rater Service,
 
6 Unified Parkinson’s Disease Rating Scale (UPDRS) 
7 Clinical Global Impression scale-Severity (CGI-S) and Clinical Global Impression scale-Improvement (CGI-I) 
 8 Any adverse event that occurs after signing the ICF and before the first dose of investigational drug is to be recorded in the updated Medical History taken on the Baseline visit 
(Day 1).  
9 Subjects will complete the Baseline RUD-Lite at the Baseline Visit and the Follow Up Visit at subsequent visits, where noted. 
10 Investigational drug is to be taken daily; on study visit days subjects should NOT take the day’s dose at home but  should wait until they are at the site and have had blood drawn 
for pimavanserin plasma level determination before taking the day’s dose. 
 
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Statistical Analysis Plan (SAP) ACP-103-015 
APPENDIX B:  Criteria for Markedly Abnormal Laboratory Values in SI 
(Système International) Units 
Lab Analyte 
Criteria 
Chemistry 
Aspartate aminotransferase 
(AST)  
≥ 3 x upper limit of normal 
Alanine Aminotransferase (ALT)  
≥ 3 x upper limit of normal 
Alkaline Phosphatase 
≥ 3 x upper limit of normal 
Lactate Dehydrogenase (LDH) 
≥ 3 x upper limit of normal 
Blood Urea Nitrogen (BUN) 
≥ 10.71 mmol/L 
Creatinine 
≥ 176.8 µmol/L 
Uric Acid 
    Males 
    Females 
≥ 619.5 µmol/L   
≥ 501.5 µmol/L 
Bilirubin (total) 
≥ 34.2  µmol/L 
Creatine Kinase (CK) 
> 3 x upper limit of normal 
Hematology 
Hematocrit 
    Males 
    Females 
≤ 0.37 and decrease of ≥ 0.03 from Baseline 
≤ 0.32 and decrease of ≥ 0.03 from Baseline 
Hemoglobin 
    Males 
    Females 
≤ 115 g/L   
≤ 95 g/L   
White Blood Count (WBC) 
≤ 2.8 x 109 /L or ≥ 16.0 x 109 /L   
Eosinophils 
≥ 10% 
Neutrophils 
Absolute Count < 1.5 x 109 /L  
Platelet Count 
≤ 100.0 x 109 /L or ≥ 700.0 x 109 /L  
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