Does Pimavanserin (Nuplazid) Improve Sleep in Patients With Parkinson Disease Psychosis? A Pilot Study
Phase: EARLY_PHASE1
Conditions: Parkinson Disease
Sponsor: State University of New York - Downstate Medical Center

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
1
 
 
 
Study Title: 
Does Pimavanserin (Nuplazid) improve sleep in patients with Parkinson disease psychosis? A 
pilot study 
 
 
NCT05796167 
 
Jan. 17, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
2
 
 
Investigator Initiated Trial Proposal 
 
Study Title: 
Does Pimavanserin (Nuplazid) improve sleep in patients with Parkinson disease psychosis? A 
pilot study 
 
Short Title: Pimavanserin for sleep in PD 
 
Therapeutic area: Parkinson disease (PD) 
 
Key study and administrative contacts: 
Daphne Robakis MD (Principal Investigator) 
Sofya Glazman (Study coordinator) 
 
Sofya Glazman is a highly experienced research coordinator, having been involved in 
clinical trial research at SUNY Downstate Health Sciences University since 2004. 
Angelika Gruessner (Biostatistician) 
Steven Levine (Research advisor) 
 
Dr. Levine is a Distinguished Professor and Vice-Chair of Neurology at SUNY Downstate 
Health Sciences University, and has extensive experience in clinical research (see CV). He will 
serve in an advisory role.  
Andrew Westwood, MD Sleep Medicine collaborator 
Motria Mishko, Pharm.D., R.Ph. is a clinical trials pharmacist  at SUNY Downstate Health 
Sciences University. Dr. Mishko will dispense study drug to the study subjects. 
 
Scientific Basis/Rationale: 
Sleep disorders are extremely common in people with Parkinson disease (PD), affecting up to 
88% of patients (1). Night-time sleep disruption and daytime sleepiness in PD can have diverse 
causes, including insomnia, restless legs syndrome (RLS), rapid eye movement (REM) sleep 
behavior disorder (RBD), medication effects, and treatment-related discomfort such as tremor 
or dyskinesia (2).  
 
Studies of sleep architecture in PD show increased arousals and sleep fragmentation, and 
reduced total sleep time and sleep efficiency.  Sleep fragmentation, or brief interruptions of 
sleep, is extremely common in PD and may be related to nocturia, medication effects, or 
hallucinations and altered dreams.  When dreaming occurs without the typical loss of muscle 
atonia during REM sleep, it leads to REM sleep behavior disorder, which affects almost half of 
PD patients (3). This disorder causes patients to physically act out their dreams, which are often 
vivid or violent, and can be dangerous for patients who may injure themselves or their bed 
partners while dreaming.  
 
 

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
3
 
The association between psychosis and RBD in PD is well established (4), as both have been 
correlated with a more widespread distribution of alpha-synuclein in the nervous system (5). In 
addition, sleep fragmentation, vivid nightmares, and RBD have been associated with the 
presence of hallucinations (6).  It is therefore a common occurrence for PD patients with visual 
hallucinations and concomitant sleep disturbance to present to the practitioner seeking 
therapeutic help. 
 
Traditional pharmacologic treatments for RBD are melatonin and clonazepam, which suffer 
from a lack of good evidence for their use, and are not completely effective in eliminating the 
symptoms of RBD (7, 8). In addition, clonazepam has risks particularly in elderly patients such as 
confusion and somnolence, and as a benzodiazepine, may be associated with an increase in 
cognitive decline and falls (9, 10). Quetiapine, an atypical antipsychotic with sedative 
properties, is often used in PD patients to treat both visual hallucinations and insomnia, but had 
no effect on sleep times as measured by PSG in a double blind study (11). Sleep fragmentation 
is often treated with similarly sedating medications. Even in patients with early stage disease 
who suffer from sleep problems, these drugs can cause unwanted side effects, particularly 
over-sedation or daytime sleepiness. Clearly, better treatments are needed for PD patients with 
sleep disorders. 
 
One potential therapeutic opportunity exists with the relatively new drug pimavanserin. 
Pimavanserin is an inverse agonist at serotonin 5-HT2A receptors that was approved by the FDA 
in 2016 for the treatment of psychotic symptoms in patients with PD (12). Limited evidence 
exists that pimavanserin may have a beneficial effect on sleep. Participants taking pimavanserin 
as part of the Phase III randomized controlled trial of psychosis in PD reported an improvement 
in nighttime sleep as detected by the SCOPA-NS sleep scale (13). In addition, pimavanserin has 
been shown to affect sleep architecture on polysomnography (PSG), particularly to increase 
slow wave sleep and decrease awakenings in healthy adults (9).  Therefore pimavanserin 
presents an opportunity for a potentially new pharmacologic treatment of sleep disorders in PD 
patients with psychotic symptoms, and perhaps for all PD patients who suffer from sleep 
disruptions.  
 
Given the lack of previous research in this area, a pilot study is proposed in order to gather 
preliminary data regarding the effect of pimavanserin on sleep quality in this patient 
population. Since sleep is a complex phenomenon, its assessment will integrate quantitative 
and subjective measures, namely PSG and a series of validated questionnaires. 
 
 
Hypothesis: 
The proposed study is feasible in terms of its design and recruitment, and will provide 
preliminary data regarding the effect of pimavanserin on sleep parameters in patients with PD 
psychosis for development of a larger trial.  
 

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
4
 
This is a feasibility study to help generate hypotheses. It is not powered for statistical 
significance. Our study size is limited by the financial resources available to us. 
 
 
Primary objective: To determine whether there is any evidence that 
pimavanserin has a beneficial effect on subjective and objective 
measures of night-time sleep in patients with PD psychosis.  
 
 
Secondary Objectives 
To inform the prospective feasibility of the current study design in 
terms of recruitment and retention. 
 
Inclusion criteria:  
1) Has a diagnosis of idiopathic PD according to UK PD Society 
Brain Bank diagnostic criteria  
2) Has a history of hallucinations or delusions associated with 
PD 
3) Has a history of sleep disturbance 
4) Is between the ages of 40 and 85 
5) Has been on a stable dose of all PD medications for at least 
30 days prior to enrolment 
 
Exclusion criteria 
1) Has evidence of an atypical or secondary parkinsonian 
disorder 
2) Has a contraindication to taking pimavanserin 
3) Has contraindication to PSG 
4) There has been a change to patient’s neuropsychiatric 
medications including dopaminergic medications (Sinemet, 
dopamine agonists, MAO-B inhibitors), SSRIs, SNRIs, 
dopamine-blocking agents, anti-epileptics, anticholinergics, 
or benzodiazepines for at least 30 days prior to enrollment  
5) Has traveled through 3 or more time zones within 60 days 
prior to study screening 
6) Patient is a night-shift worker 
 
Primary endpoint: 
Evidence of a change pre and post- drug treatment in sleep 
architecture as seen on PSG in terms of 1) REM Sleep without atonia 
(RSWA) 2) number of arousals 
 

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
5
 
Secondary endpoints: 
1) A change in other PSG parameters pre and post-treatment 
including:  
a) Sleep latency 
c) wake after sleep onset 
d) total sleep time 
e) sleep efficiency 
f)  time in each sleep stage (N1 N2 N3, REM) 
2) Change in qualitative sleep and RBD self-assessments 
(RBDSQ, PDSS-2 and PFS-16).  
3) Recruitment and adherence rates 
 
Trial Design check boxes: Other 
 
If other, please specify: 
This study uses a self-control design. A similar design was used to study the effect of LCIG on 
sleep in PD (14). 
At baseline/screening and after 6 weeks of treatment with pimavanserin, the following 
assessments will be completed:  
i) Polysomnography (PSG) 
ii) Sleep questionnaires:  
a. Parkinson’s Disease Sleep Scale, 2nd version (PDSS-2) 
b. Parkinson’s disease Fatigue scale (PFS-16) 
c. RBD sleep questionnaire (RBDSQ) 
d. MDS Unified Parkinson’s disease rating scale (MDS-UPDRS) 
e. The Montreal Cognitive assessment (MOCA) (administered at baseline/screening 
only)  
At baseline/screening, the following study will be done: 
i) 
EKG 
 
 
 
Study Phase: 
If Other, please specify: Pilot study 
Number of Sites: 1 
 
Sample size justification/Statistical Analysis: 
Estimated number of patients: 10 patients will be enrolled from SUNY Downstate Health 
Sciences University. As this is a pilot study, there are no formal sample size calculations and 
power estimates. Estimating a drop-out rate of 10% due to adverse effects as seen in previous 
studies with pimavanserin (15), we will aim to recruit and enroll a total of 10 patients (our 
budget therefore assumes a total of 10 patients). If necessary, more participants will be added  

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
6
 
to maintain a total of 10 participants with complete data.   
 
Study drug related issues: 
The standard dose of Pimavanserin (Nuplazid) 34mg capsules oral daily will be used in this 
study. Patients will be treated for 6 weeks in keeping with prior studies to ensure adequate 
treatment duration (12). Using the above estimate for number of patients to be enrolled: 1 
tablet per day x 10 patients x 42 days = 420 capsules will be requested. 
 
 
Estimated Duration of study:  
Year 1 
Months 1-3: Administrative set-up, IRB submission and approval, set up screening protocols, 
role out study awareness within the recruiting hospitals, subject recruitment 
Months 4-12: Subject enrollment and ongoing recruitment 
Goal 50% enrollment by end of year 1 
Year 2 
Months 1-6: Subject enrollment  
Months 7-9: Complete all study visits and subject follow-up; clean, edit, and lock study 
database 
Months 10-12: Data analyses, manuscript preparation and submission  
 
Study visits procedures:  
 
Visit 1 – Screening/Baseline  
1) Informed Consent 
2) Screening for inclusion/exclusion criteria 
Vital Signs (blood pressure, pulse, height and weight) 
medical history, personal information (date of birth, gender, race/ethnicity) and 
medications taken (including over-the-counter) 
3) Clinical Evaluation 
a. Parkinson’s Disease Sleep Scale, 2nd version (PDSS-2) 
b. Parkinson’s disease Fatigue scale (PFS-16) 
c. RBD sleep questionnaire (RBDSQ) 
d. MDS Unified Parkinson’s disease rating scale (MDS-UPDRS) 
e. The Montreal Cognitive assessment (MOCA) (administered at baseline only) 
f. EKG  
4) Dispense study drug  if a patient is eligible for the study 
5) A subject will be scheduled for Polysomnography (PSG), sleep study, at United Sleep 
Diagnostics, Inc.                                                                                                                                      
PSG  records the changes that occur during sleep, e.g., number of arousals, sleep 
latency,  wake after sleep onset, total sleep time, sleep efficiency, time in each sleep 
stage.                                                                                                                                                                    

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
7
 
The PSG monitors brain activity (EEG - electroencephalography), eye movements (EOG - 
electrooculography), muscle activity (EMG - electromyography), and heart rhythm (ECG 
- electrocardiography)                                                                                                                                    
A subject will report to the United Sleep Diagnostics located at 808 8th Ave, Brooklyn NY 
11215 at 8 pm on the scheduled date for the sleep study and stay overnight.                                          
A sleep technician will attach the electrodes (metal discs) to a subject’s skin and monitor 
a subject during the study.                                                                                                                      
The report will be sent to the study doctor for analysis. 
 
 
 
Visit 2 - Baseline PSG (same day as Screening/Baseline) 
1) Polysomnography will be done at United Sleep Diagnostics clinic 
2) Start study drug Day 1 
 
Visit 3 - Phone Call Week 2 
1) Phone visit with Study coordinator to evaluate how a study participant tolerates 
the study drug and how it is affecting his/her Parkinson’s symptoms; review of 
current medications 
 
Visit 4 - Follow-up PSG Week 6 
1) Polysomnography 
 
Visit 5 -Week 6 (same day as PSG)/Early Withdrawal 
1) Clinical Evaluation 
a. Parkinson’s Disease Sleep Scale, 2nd version (PDSS-2) 
b. Parkinson’s disease Fatigue scale (PFS-16) 
c. RBD sleep questionnaire (RBDSQ) 
d. MDS Unified Parkinson’s disease rating scale (MDS-UPDRS) 
 
2) Return of empty study drug bottle and unused study drug 
 
A study participant will be reimbursed after Visit 2 Baseline PSG of $200 ($50 for Visit 1 
Screening/Baseline; $150 for Visit 2 Baseline PSG). Then a study participant will be reimbursed 
after Visit 5 6 weeks/Early Withdrawal of $350 ($150 for Visit 4 Follow-up PSG 6 weeks; $200 
for Visit 5 6 weeks/Early Withdrawal). 
A check will be mailed to a study participant. 
If a study participant leaves the study early, he/she will be reimbursed only for visits that 
he/she completes. 
 
 
 

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
8
 
A plan to monitor conduct of the study at the site 
 
Because this is Investigator-Initiated study, the PI/sponsor-investigator, Daphne Robakis, MD 
understands her responsibility for  
oversight of the study, and takes responsibility for any unanticipated problems or serious or 
continuing non-compliance; 
attends a study “kickoff” meeting; 
will be responsible for reporting any reportable events that occur; 
conducts site initiation visit with all study staff to provide any needed training on study 
protocol; 
is responsible to address any issues that arise; 
will conduct conference calls with all study staff; agenda and minutes will be recorded and filed; 
will assess all SAEs. 
 
 
Investigator comments: 
Dr. Robakis and her study team have extensive experience in academic clinical research.  
Dr. Robakis completed her fellowship at Columbia University under the tutelage of Stanley 
Fahn. During her fellowship she also received instruction in clinical trials research from  
Dr. Cheryl Waters. Her first academic faculty position was at Yale University where she was 
mentored by Dr. Elan Louis, who has an extensive publication record in the field of movement 
disorders. Currently, she works closely with Dr. Steven Levine, the Vice-Chair of Neurology at 
SUNY Downstate Health Sciences University and a nationally recognized researcher. Dr. Robakis 
is currently involved in clinical research at SUNY Downstate Health Sciences University, 
including a translational research project funded by the Michael J. Fox Foundation, and a multi-
site clinical drug trial for PD. In addition, her scholarship encompasses mentoring resident 
physician research and forging collaborations with faculty. To further strengthen the study 
team, two additional academic neurologists in the field of movement disorders and sleep 
medicine with proven track records in clinical research will be consulted to help guide the study 
set-up and manuscript publication. 
 
Please note that the clinical portion of this study will take place at SUNY Downstate Health 
Sciences University Neurology Department. The sleep study will be performed at the United 
Sleep Diagnostics lab.  
 
The study will be advertised on the e-screens around the SUNY Downstate Health Sciences 
University campus. 
 
There is no intent to seek a new indication for the drug. 
 
 

Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
9
AE / SAE Reporting: 
 
To Report all adverse events directly to the FDA in accordance with 
applicable law and Study protocol. 
 
All serious adverse events (SAE) must be reported to Acadia Call 
Center at 1-844-4-Acadia (1-844-422-2342) within 24 hours of such 
SAE. 
A copy of any reports to the FDA (e.g. SUSAR) will be sent to Acadia at 
the time of submission to the FDA. 
All complaints (product complaints or product grievances), regardless 
of origin, must be reported to the Acadia Call Center at 1-844-4-
Acadia (1-844-422-2342). 
 
 
 
 
 
Describe support: 
None 
 
Planned Publications: Does pimavanserin improve sleep in patients with Parkinson disease 
psychosis? A pilot study     
 
 
SUPPORT: 
Funding Support: Acadia Pharmaceuticals, Inc. 
Product Request: Emily Mull; emull@acadia-pharm.com 
Legal/contracting information:  Ernest Purefied;  ernest.purefied@downstate.edu 
Shipping Site information:  
Motria Mishko 
SUNY Downstate Health Sciences University 
450 Clarkson Ave, MSC  36 
Pharmacy Department  
Brooklyn, NY 11203 
 
 
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Daphne Robakis, MD  
 
SUNY Downstate Health Sciences University 
Unique Identifier: 1396075255                                      01.17.2023 
NCT05796167 
 
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