C-SAPP: Pimavanserin vs. Quetiapine for Treatment of Parkinson's Psychosis

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Not yet recruiting

CT.gov ID

NCT04373317

Collaborator

(none)

358

Enrollment

Locations

Arms

Anticipated Duration (Months)

14.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Patients with Parkinson's disease (PD) sometimes experience symptoms affecting their movement, such as slowness, tremor, stiffness, and balance or walking problems. Many patients also have other symptoms not related to movement, called non-motor symptoms, which may affect one's mood or emotions, memory or thinking, or cause one to see or hear things that aren't real (hallucinations) or believe things that aren't true (delusions). Hallucinations or delusions, together called psychosis, occur in up to 60% of PD patients at some point in time. Parkinson's disease psychosis can sometimes be associated with decreased quality of life, increased nursing home placement, increased rate of death, and greater caregiver burden. There are approximately 50,000 Veterans with Parkinson's disease receiving care in the VA, and up to 30,000 (60%) of them will experience psychosis at some point in time.

Quetiapine is an antipsychotic drug approved by the Food and Drug Administration (FDA) that is the most commonly used medication to treat PD psychosis, but more studies are needed to determine if it works for this condition and is also well tolerated and safe. Pimavanserin is a newer antipsychotic drug approved by the Food and Drug Administration (FDA) specifically to treat PD psychosis, but more studies are needed to determine if it works and its safety.

The purpose of this research is to gather additional information on the safety and effectiveness of both Quetiapine and Pimavanserin. By doing this study, the investigators hope to learn which of these medications is the most effective course of treatment for people with PD psychosis.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease Psychosis	Drug: Pimavanserin Drug: Quetiapine	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

358 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Two active treatments will be administered in this RCT, with 1:1 treatment assignment to either quetiapine or pimavanserin. Both active treatments are FDA-approved antipsychotics.Two active treatments will be administered in this RCT, with 1:1 treatment assignment to either quetiapine or pimavanserin. Both active treatments are FDA-approved antipsychotics.

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

In order to facilitate titrations, study drug will be provided in blister cards with a sufficient number of over-encapsulated drug to bridge participants to their next titration step. Each blister card will contain a one-week supply of study drug. Because dosing will be nightly, and the study will use a combination of quetiapine strengths for all protocol-specified quetiapine doses, participants in both treatment groups will take two identical capsules both of which containing the protocol-specified nightly dose. For example, if a participant is randomized to quetiapine and is up-titrated from 50 to 100 mg ER, this participant will take 2 identical capsules, each containing 50 mg of ER quetiapine. Similarly, participants randomized to pimavanserin will take two capsules every night, one containing a placebo capsule, and the other containing 34 mg of pimavanserin.

Primary Purpose:

Treatment

Official Title:

CSP #2015 - Multicenter, Randomized, Double-blind Comparator Study of Antipsychotics Pimavanserin and Quetiapine for Parkinson''s Disease Psychosis (C-SAPP)

Anticipated Study Start Date :

Oct 1, 2022

Anticipated Primary Completion Date :

Oct 1, 2025

Anticipated Study Completion Date :

Aug 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pimavanserin 34mg All participants assigned to pimavanserin will receive the FDA-approved dose of 34mg (equivalent to 40 mg pimavanserin tartrate) daily without titration; however, because pimavanserin is blinded to quetiapine, participants will undergo sham titration based on tolerability.	Drug: Pimavanserin Fixed-dose Pimavanserin - Pimavanserin is a new antipsychotic agent, and pure 5HT-2A inverse agonist, that was approved by the FDA recently (2016) for the treatment of PDP. It is the only FDA-approved medication for PDP, but is still not the first-line AP used in PD. All participants assigned to pimavanserin will receive the FDA-approved dose of 34 mg (equivalent to 40 mg pimavanserin tartrate) daily without titration up or down; however, because pimavanserin is blinded to quetiapine, participants will undergo sham titration based on tolerability (i.e., overall adverse event profile) and efficacy (i.e., improvement in severity of psychosis).
Active Comparator: Quetiapine Quetiapine extended release will be titrated as shown in the following table. During the 8-week treatment phase, there is a maximum of 6 weeks for titration. Titration Schedule Visit/call Quetiapine Dose (Flexible)Quetiapine Notes Baseline visit (Visit 00)25 mg IR QHSAll participants must be up-titrated to at least 50 mg/day at week 1 Week 1 call (Visit 01)50 mg XR QHSUp-titration Week 3 visit (Visit 03)100 mg XR QHS (requiring two 50-mg quetiapine XR capsules)Up- or down-titration as appropriate based on psychosis symptoms and tolerability Week 5 visit (Visit 05)150 mg quetiapine XR QHSUp- or down-titration as appropriate based on psychosis symptoms and tolerability Week 6 call (Visit 06)200 mg quetiapine XR QHSUp- or down-titration as appropriate based on psychosis symptoms and tolerability	Drug: Quetiapine Flexible-dose Quetiapine - Quetiapine, which is a mixed serotonin and dopamine receptor antagonist, is by far the most commonly used AP for PDP. However, scientific evidence for the efficacy of quetiapine in PDP is almost non-existent as most of the studies were underpowered, had high drop-out rates, and possibly underdosed quetiapine. Quetiapine immediate and extended release will be titrated as shown: Baseline visit Quetiapine: 25 mg IR QHS, All participants must be up-titrated to 50 mg/day Pimavanserin: 34 mg QHS Week 1 call Quetiapine: 50 mg XR QHS, Up-titration to 50 mg Pimavanserin: 34 mg QHS Week 3 visit Quetiapine: 100 mg XR QHS, Up-titration as appropriate Pimavanserin: 34 mg QHS Week 5 visit Quetiapine: 150 mg XR QHS, Up- or down-titration as appropriate Pimavanserin: 34 mg QHS Week 6 call Quetiapine: 200 mg XR QHS, Up- or down-titration as appropriate Pimavanserin: 34 mg QHS

Arm

Intervention/Treatment

Active Comparator: Pimavanserin 34mg

All participants assigned to pimavanserin will receive the FDA-approved dose of 34mg (equivalent to 40 mg pimavanserin tartrate) daily without titration; however, because pimavanserin is blinded to quetiapine, participants will undergo sham titration based on tolerability.

Drug: Pimavanserin

Fixed-dose Pimavanserin - Pimavanserin is a new antipsychotic agent, and pure 5HT-2A inverse agonist, that was approved by the FDA recently (2016) for the treatment of PDP. It is the only FDA-approved medication for PDP, but is still not the first-line AP used in PD. All participants assigned to pimavanserin will receive the FDA-approved dose of 34 mg (equivalent to 40 mg pimavanserin tartrate) daily without titration up or down; however, because pimavanserin is blinded to quetiapine, participants will undergo sham titration based on tolerability (i.e., overall adverse event profile) and efficacy (i.e., improvement in severity of psychosis).

Active Comparator: Quetiapine

Quetiapine extended release will be titrated as shown in the following table. During the 8-week treatment phase, there is a maximum of 6 weeks for titration. Titration Schedule Visit/call Quetiapine Dose (Flexible)Quetiapine Notes Baseline visit (Visit 00)25 mg IR QHSAll participants must be up-titrated to at least 50 mg/day at week 1 Week 1 call (Visit 01)50 mg XR QHSUp-titration Week 3 visit (Visit 03)100 mg XR QHS (requiring two 50-mg quetiapine XR capsules)Up- or down-titration as appropriate based on psychosis symptoms and tolerability Week 5 visit (Visit 05)150 mg quetiapine XR QHSUp- or down-titration as appropriate based on psychosis symptoms and tolerability Week 6 call (Visit 06)200 mg quetiapine XR QHSUp- or down-titration as appropriate based on psychosis symptoms and tolerability

Drug: Quetiapine

Flexible-dose Quetiapine - Quetiapine, which is a mixed serotonin and dopamine receptor antagonist, is by far the most commonly used AP for PDP. However, scientific evidence for the efficacy of quetiapine in PDP is almost non-existent as most of the studies were underpowered, had high drop-out rates, and possibly underdosed quetiapine. Quetiapine immediate and extended release will be titrated as shown: Baseline visit Quetiapine: 25 mg IR QHS, All participants must be up-titrated to 50 mg/day Pimavanserin: 34 mg QHS Week 1 call Quetiapine: 50 mg XR QHS, Up-titration to 50 mg Pimavanserin: 34 mg QHS Week 3 visit Quetiapine: 100 mg XR QHS, Up-titration as appropriate Pimavanserin: 34 mg QHS Week 5 visit Quetiapine: 150 mg XR QHS, Up- or down-titration as appropriate Pimavanserin: 34 mg QHS Week 6 call Quetiapine: 200 mg XR QHS, Up- or down-titration as appropriate Pimavanserin: 34 mg QHS

Outcome Measures

Primary Outcome Measures

CGI-I Psychosis [8 Weeks]
The Clinical Global Impressions (CGI) scale is a brief, well-established research rating tool used to quantify and track patient progress and treatment response over time. The CGI comprises two measures, one of which is Improvement (CGI-I) from the initiation of treatment. It is scored 1 to 7. The CGI-I is used to assess how much the patient's illness has improved or worsened relative to baseline when the intervention was started (1-Very much improved, 2-Much improved, 3-Minimally improved, 4-No change, 5-Minimally worse, 6-Much worse, 7-Very much worse). The CGI-I can also be used to assess specific domains, including psychosis (this study's primary outcome) and parkinsonism (a secondary outcome). During the 8 weeks, the CGI-I (for psychosis, hereafter simply referred to as the CGI-I) will be administered to all participants at each in-person visit (3 weeks, 5 weeks, and 8 weeks following a CGI-I baseline interview) to assess clinical improvement in psychosis.

Secondary Outcome Measures

SAPS-PD [8 Weeks]
The primary assessment of change in psychosis severity is the score on the 9-item Parkinson's disease Scale for Assessment of Positive Symptoms (SAPS-PD). The SAPS-PD scale will assess positive symptoms, including hallucinations, delusions, bizarre behavior, and positive formal thought disorder. A clinical interview is used to evaluate the participant's symptoms. Items include: 1 Auditory Hallucinations; 2 Voices Conversing; 3 Somatic or Tactile Hallucinations; 4 Visual Hallucinations; 5 Global Rating of Severity of Hallucinations; 6 Persecutory Delusions; 7 Delusions of Jealousy; 8 Ideas and Delusions of Reference; and 9 Global Rating of Severity of Delusions. Each item is given a score ranging 0 to 5 (0-None, 1-Questionable, 2-Mild, 3-Moderate, 4-Marked, 5-Severe). During the 8 weeks, the SAPS-PD will be administered to all participants at each in-person visit (baseline, 3 weeks, 5 weeks, and 8 weeks) to assess symptoms of PDP and psychopharmacological response to treatment.
MDS-UPDRS III [8 Weeks]
The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (Motor Examination; MDS-UPDRS III) has 33 scores across 18 items (each score 0-4, range of total score 0-132, with higher scores indicating more severe motor symptoms) is completed by a trained rater during an examination of the patient, and is the most commonly-used assessment of parkinsonism in clinical trials. MDS-UPDRS III includes ratings for tremor, slowness (bradykinesia), stiffness (rigidity), and gait/balance. During the 8 weeks, the MDS-UPDRS III will be administered to all participants at each in-person visit (baseline, 3 weeks, 5 weeks, and 8 weeks).
Zarit Caregiver Burden Scale [8 Weeks]
The Zarit Burden Interview (ZBI) is a 22-item self-report inventory that examines burden associated with functional/behavioral impairments and the home care situation. It was developed to measure subjective burden among caregivers of adults with dementia. The items are worded subjectively, focusing on the affective response of the caregiver. Each question is scored on a 5-point Likert scale ranging from 0 to 4 (0-Never, 1-Rarely, 2-Sometimes, 3-Frequently, 4-Nearly always). The ZBI total score ranges from 0 (low burden) to 88 (high burden), the sum of the scores from all 22 questions. Interpretation of the total scores is: 1) 0-21 little or no burden; 2) 21-40 mild to moderate burden; 3) 41-60 moderate to severe burden; and 4) 61-88 severe burden. The ZBI will be administered to all participants' informed other at baseline and treatment phase visits of Weeks 5 and 8.
CGI-I Parkinsonism [8 Weeks]
The Clinical Global Impressions (CGI) scale is a brief, rating tool used to quantify and track patient progress and treatment response over time. It was developed to be used in clinical trials on mental health to provide an assessment of the clinician's view of the patient's global functioning over time with a study medication. The CGI comprises two measures, but the one to be used in this study is Improvement (CGI-I) from the st of treatment. It is scored from 1 to 7. The CGI-I is used to assess how much the patient's illness has improved or worsened relative to baseline when the intervention was started (1-Very much improved, 2-Much improved, 3-Minimally improved, 4-No change, 5-Minimally worse, 6-Much worse, 7-Very much worse). During the 8 weeks, the CGI-I (for parkinsonism) will be administered to all participants at each in-person visit (3 weeks, 5 weeks, and 8 weeks following a CGI-I baseline interview) to assess improvement in parkinsonism.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Veteran
Age 40 years or older
Diagnosis of Parkinson's Disease consistent with UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria
Psychosis [with Neuropsychiatric Inventory (NPI) hallucinations (B) or delusions (A) score 4 or greater]
Stable dose of PD medications for at least 1 month
If on an acetylcholinesterase inhibitor (AChEI) initially prescribed at least 3 months prior and stable dose (no dose or medication change) for past month
Informed other must provide informed consent and agree to attend all study visits. The informed other must be at least 18 years of age and have regular in-person contact with the patient (at least 5 days per week, and at least 4 hours per day that is spent with patient)
English-speaking

INFORMED OTHER

Age 18 years or older
Must have regular in-person contact with the patient (on average at least 5 days per week, and at least 4 hours per day that is spent with patient)
Agree to attend all study visits
Be able to provide informed consent
English-speaking

Exclusion Criteria:

Psychosis symptoms severe enough to preclude enrollment in a clinical trial and require prompt clinical care instead
Treatment with an antipsychotic, including pimavanserin in the past year, except quetiapine <50 mg/day which has been discontinued for at least 1 month prior to study randomization
Deep brain stimulation (DBS) surgery occurring within 6 months prior or has had stimulator adjustments in the previous month
History of a psychotic disorder prior to PD, including schizophrenia and bipolar disorder
Suspected atypical parkinsonian disorder or dementia with Lewy bodies (DLB)
Psychosis secondary to other toxic or metabolic disorder
History of long QT syndrome
Prolonged QTc [>450ms in men, >470ms in women] at screening
History of ventricular arrhythmias, or untreated or unstable atrial fibrillation/flutter
Currently taking medications that are moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors
Concomitant use of drugs that prolongs the QTc interval
Comorbid medical condition determined too severe by SI to allow participation in clinical trial
Failure to tolerate quetiapine or pimavanserin previously
Moderate to severe PD dementia (MoCA score <13)
Currently enrolled in another therapeutic or interventional study
Nursing home placement at screening or planned placement during the study
Active suicidality
Pregnant, or a female of child-bearing potential who is unwilling to use a reliable form of contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern Arizona VA Health Care System, Tucson, AZ	Tucson	Arizona	United States	85723
2	VA Loma Linda Healthcare System, Loma Linda, CA	Loma Linda	California	United States	92357
3	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California	United States	90822
4	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California	United States	94304-1290
5	VA San Diego Healthcare System, San Diego, CA	San Diego	California	United States	92161
6	San Francisco VA Medical Center, San Francisco, CA	San Francisco	California	United States	94121
7	VA Greater Los Angeles Healthcare System, West Los Angeles, CA	West Los Angeles	California	United States	90073
8	James A. Haley Veterans' Hospital, Tampa, FL	Tampa	Florida	United States	33612
9	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois	United States	60141-5000
10	Lexington VA Medical Center, Lexington, KY	Lexington	Kentucky	United States	40502
11	VA Ann Arbor Healthcare System, Ann Arbor, MI	Ann Arbor	Michigan	United States	48105
12	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota	United States	55417
13	St. Louis VA Medical Center John Cochran Division, St. Louis, MO	Saint Louis	Missouri	United States	63106
14	New Mexico VA Health Care System, Albuquerque, NM	Albuquerque	New Mexico	United States	87108-5153
15	Syracuse VA Medical Center, Syracuse, NY	Syracuse	New York	United States	13210
16	Asheville VA Medical Center, Asheville, NC	Asheville	North Carolina	United States	28805
17	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio	United States	44106
18	VA Portland Health Care System, Portland, OR	Portland	Oregon	United States	97239
19	Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA	Philadelphia	Pennsylvania	United States	19104
20	Philadelphia MultiService Center, Philadelphia, PA	Philadelphia	Pennsylvania	United States	19106
21	Tennessee Valley Healthcare System Nashville Campus, Nashville, TN	Nashville	Tennessee	United States	37212-2637
22	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas	United States	77030
23	South Texas Health Care System, San Antonio, TX	San Antonio	Texas	United States	78229
24	Hunter Holmes McGuire VA Medical Center, Richmond, VA	Richmond	Virginia	United States	23249
25	VA Puget Sound Health Care System Seattle Division, Seattle, WA	Seattle	Washington	United States	98108