Pimavanserin vs. Quetiapine for Psychosis in Parkinson's Disease

(C-SAPP Trial)

Recruiting at 18 trial locations

Overseen By John E Duda, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must not be taking: Antipsychotics, CYP3A4 inducers, others

Disqualifiers: Severe psychosis, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: 8 weeks

358 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you have not been treated with an antipsychotic, including pimavanserin, in the past year, except for quetiapine at less than 50 mg/day, which must be stopped at least 1 month before joining the study. If you are taking medications that affect the heart's rhythm or certain other drugs, you may need to stop those as well.

What data supports the effectiveness of the drug quetiapine for treating psychosis in Parkinson's disease?

Research shows that quetiapine can effectively reduce psychotic symptoms like hallucinations and delusions in patients with Parkinson's disease, without worsening their motor symptoms. It is well-tolerated and can also improve cognitive functions, making it a viable option for managing psychosis in these patients. ^{1 2 3 4 5}

Is Pimavanserin safe for treating psychosis in Parkinson's disease?

Pimavanserin has been associated with an increased risk of death in some reports, but when compared to other treatments for Parkinson's disease psychosis, it did not show an excess of death reports. It's important to discuss the risks and benefits with your doctor. ^{1 6 7 8 9}

How is the drug pimavanserin different from other drugs for Parkinson's disease psychosis?

Pimavanserin is unique because it is the only FDA-approved drug specifically for treating hallucinations and delusions in Parkinson's disease psychosis, unlike quetiapine, which is used off-label. Pimavanserin works by targeting serotonin receptors, which helps manage psychosis without worsening Parkinson's motor symptoms. ^{1 2 7 10 11}

Research Team

Daniel Weintraub, MD

Principal Investigator

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Eligibility Criteria

This trial is for Veterans with Parkinson's Disease who are experiencing psychosis, such as hallucinations or delusions. Participants must be English-speaking adults over 40 years old, have regular contact with a caregiver, and not live in a nursing home. They can't have used certain antipsychotics recently, have heart rhythm problems, severe dementia or other disqualifying conditions.

Inclusion Criteria

I have been diagnosed with Parkinson's Disease.

I've been on a stable dose of an acetylcholinesterase inhibitor for at least 4 months.

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)

Exclusion Criteria

You had a mental health condition like schizophrenia or bipolar disorder before Parkinson's disease.

My psychosis is due to a toxic or metabolic disorder.

I couldn't tolerate quetiapine or pimavanserin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Quetiapine or Pimavanserin for Parkinson's Disease Psychosis. Quetiapine is titrated over 6 weeks, while Pimavanserin is administered at a fixed dose with sham titration.

8 weeks

4 visits (in-person) at baseline, 3 weeks, 5 weeks, and 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pimavanserin
• Quetiapine

Trial Overview The study compares the safety and effectiveness of two antipsychotic drugs: Quetiapine (commonly used but not FDA-approved for PD psychosis) versus Pimavanserin (newer and FDA-approved specifically for PD psychosis). The goal is to determine which drug works best for treating psychosis in Parkinson's patients.

Participant Groups

Group I: Quetiapine Active Control 1 Intervention

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

Group II: Pimavanserin 34mg Active Control 1 Intervention

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.

Pimavanserin is already approved in United States for the following indications:

Approved in United States as Nuplazid for:

• Hallucinations and delusions associated with Parkinson's disease psychosis

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

In a study of 27 patients with Parkinson's disease and recent-onset psychosis, both quetiapine and clozapine were found to be effective treatments, with no worsening of parkinsonism observed during the 22-week treatment period.

Clozapine showed a greater ability to reduce delusions and had a trend towards better control of hallucinations compared to quetiapine, but it also posed a risk of leukopenia, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson's disease psychosis. Merims, D., Balas, M., Peretz, C., et al.[2022]

In a study of 10 patients with Parkinson's disease experiencing psychosis due to antiparkinsonian drugs, quetiapine effectively eliminated psychotic symptoms in 9 out of 10 patients.

Quetiapine was associated with no significant worsening of parkinsonism, highlighting its safety and efficacy as a treatment for psychosis in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of quetiapine fumarate on drug-induced psychosis in patients with Parkinson's disease]. Kohmoto, J., Kihira, T., Miwa, H., et al.[2015]

In three case histories of Parkinson's disease patients who had to stop clozapine, switching to quetiapine resulted in behavioral improvements without significantly worsening motor symptoms, indicating its potential as a safer alternative.

Quetiapine was well tolerated at doses ranging from 12.5 to 150 mg/day, suggesting it may effectively manage psychosis and agitation in Parkinson's disease patients while minimizing the risk of exacerbating parkinsonism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quetiapine as an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease. Menza, MM., Palermo, B., Mark, M.[2019]

In a study of 11 patients with Parkinson's disease and acute psychosis, quetiapine was found to be effective in controlling visual hallucinations in 6 patients, demonstrating its potential as a treatment option for psychotic symptoms in this population.

Quetiapine was well tolerated overall, with no exacerbation of parkinsonian symptoms observed, suggesting that atypical antipsychotics may be safer alternatives for managing psychosis in patients with Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of quetiapine in Parkinson's patients with psychosis. Targum, SD., Abbott, JL.[2019]

In a 24-week trial involving 29 elderly patients with Parkinson's disease who did not respond to other antipsychotics, quetiapine significantly improved psychotic symptoms without worsening motor function.

Patients showed notable improvements in psychiatric assessments and cognitive recall, indicating that quetiapine is both effective and well-tolerated for treating psychosis in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quetiapine improves psychotic symptoms and cognition in Parkinson's disease. Juncos, JL., Roberts, VJ., Evatt, ML., et al.[2015]

Pimavanserin is an atypical antipsychotic that effectively treats hallucinations and delusions in Parkinson's disease without worsening motor symptoms, based on a review of 2 published randomized controlled trials.

While only 1 of the 4 trials showed significant improvement in psychotic symptoms compared to placebo, pimavanserin's selective action on serotonin 5-HT2a receptors suggests it may be a more tolerable treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin (Nuplazid™) for the treatment of Parkinson disease psychosis: A review of the literature. Touma, KTB., Touma, DC.[2022]

Pimavanserin (PIM) treatment for Parkinson's Disease Psychosis (PDP) is associated with significantly lower rates of all-cause hospitalizations and psychiatric-related inpatient hospitalizations compared to quetiapine (QUE), suggesting it may be a safer option for managing PDP.

In a study of over 8,000 patients, those on PIM had a 22% reduction in all-cause hospitalizations and a 37% reduction in psychiatric-related hospitalizations, indicating its potential efficacy in reducing healthcare resource utilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients treated with pimavanserin or quetiapine for Parkinson's disease psychosis: analysis of health resource utilization patterns among Medicare beneficiaries. Rajagopalan, K., Rashid, N., Doshi, D.[2023]

Pimavanserin is a selective serotonin 2A receptor inverse agonist that has been approved in the US specifically for treating hallucinations and delusions in patients with Parkinson's disease psychosis, a condition affecting up to 60% of Parkinson's patients.

The approval of pimavanserin is significant as it provides a treatment option for a condition that has limited therapeutic alternatives and is associated with increased morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin: First Global Approval. Markham, A.[2022]

A retrospective analysis of 2,287 death reports associated with pimavanserin found that while it had a higher proportional reporting ratio (PRR) for death in the general population, this signal diminished significantly when focusing on patients with Parkinson's disease (PD), indicating no excess mortality risk compared to other treatments.

The study suggests that pimavanserin's safety profile is comparable to other antipsychotics for PD patients, and the findings should inform shared decision-making between physicians and patients regarding the risks and benefits of using pimavanserin for PD-related psychosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis. Brown, JD., Cicali, B., Henriksen, C., et al.[2023]

Pimavanserin is a safe and effective option for patients with Parkinson's disease psychosis (PDP) who are switching from atypical antipsychotics like quetiapine or clozapine, based on expert consensus and pharmacological considerations.

The recommended approach for switching involves adding pimavanserin at the full dose (34 mg) for 2-6 weeks while tapering off the previous medication, ensuring continued efficacy and minimizing withdrawal effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus. Black, KJ., Nasrallah, H., Isaacson, S., et al.[2019]

Pimavanserin is the only FDA-approved medication specifically for treating hallucinations and delusions in Parkinson's disease psychosis, highlighting its importance in managing this serious nonmotor complication.

While off-label use of clozapine and quetiapine shows some effectiveness, there is a critical need for new treatments to minimize side effects and alleviate the financial and emotional burdens of Parkinson's disease psychosis on patients and caregivers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Parkinson's Disease Psychosis. Elsibai, H., Kualleny, M., Fandy, TE.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson's disease psychosis. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

[Effect of quetiapine fumarate on drug-induced psychosis in patients with Parkinson's disease]. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Quetiapine as an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Efficacy of quetiapine in Parkinson's patients with psychosis. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Quetiapine improves psychotic symptoms and cognition in Parkinson's disease. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

Pimavanserin (Nuplazid™) for the treatment of Parkinson disease psychosis: A review of the literature. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Patients treated with pimavanserin or quetiapine for Parkinson's disease psychosis: analysis of health resource utilization patterns among Medicare beneficiaries. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Pimavanserin: First Global Approval. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Management of Parkinson's Disease Psychosis. [2022]