Pimavanserin for PTSD-Related Insomnia

(PIP-II Trial)

Overseen By Ricardo E Jorge, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must not be taking: Hypnotics, Antipsychotics, CYP3A4 inhibitors, others

Disqualifiers: Psychotic disorders, Substance use, Sleep apnea, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a preliminary randomized, double-blind, placebo-controlled trial comparing pimavanserin 34mg at bedtime vs. placebo for the treatment of insomnia associated with post-traumatic stress disorder.

Do I need to stop my current medications to join the trial?

You may need to stop certain medications before joining the trial. Specifically, hypnotics or sedating medications taken at bedtime, as well as some antipsychotics and antidepressants, must be stopped for 1 week before enrollment. However, you can continue taking SSRIs, SNRIs, bupropion, and some anticonvulsants if they have been stable for at least a month.

How is the drug pimavanserin unique for treating PTSD-related insomnia?

Pimavanserin is unique because it targets the 5-HT2A serotonin receptors, which may play a role in anxiety and emotional memory, potentially reducing PTSD-related symptoms. Unlike other treatments, it is a selective serotonin receptor inverse agonist, which has been used for treating hallucinations and delusions in Parkinson's disease psychosis, suggesting a novel approach for PTSD-related insomnia. ^{1 2 3 4 5}

Research Team

Melissa B Jones, MD

Principal Investigator

Michael E. DeBakey VA Medical Center, Houston, TX

Eligibility Criteria

This trial is for male and female Veterans aged 18-64 with chronic insomnia and PTSD. Participants must meet specific sleep dissatisfaction criteria, have stable PTSD symptoms, not start other treatments during the study, and agree to contraception if applicable. Exclusions include psychotic disorders, substance abuse, certain brain injuries or neurological illnesses, some cardiovascular conditions, pregnancy or breastfeeding.

Inclusion Criteria

Acceptable methods of contraception for sexually active women of child-bearing potential

Meets DSM-5 standards of chronic insomnia disorder with specific criteria including dissatisfaction with nighttime sleep, insomnia frequency, duration of insomnia complaint, daytime impairment, moderate insomnia severity, clinically significant PTSD symptoms, willingness to comply with protocol, and agreement to contraception for women of child-bearing potential

I agree not to begin any new treatments for insomnia, PTSD, or other mental health issues during the study.

Exclusion Criteria

I have been diagnosed with a sleep disorder or obstructive sleep apnea.

I have a condition that increases my risk of sudden heart-related death.

I have stopped taking certain mental health meds and strong CYP3A4 drugs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either pimavanserin 34mg or placebo at bedtime for 8 weeks

8 weeks

Weekly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pimavanserin
• Placebo

Trial Overview The trial tests pimavanserin (34mg at bedtime) against a placebo in treating insomnia linked to PTSD. It's randomized and double-blind; neither participants nor researchers know who gets the real drug versus the placebo until after results are collected.

Participant Groups

Group I: Pimavanserin 34mg PO at bedtime Active Control 1 Intervention

Pimavanserin 34mg is taken by mouth at bedtime for 8 weeks .

Group II: Placebo PO at bedtime Placebo Group 1 Intervention

The active study medication listed above will be compared with a placebo, which is a pill that looks like a study medication but has no medication in it

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+

ACADIA Pharmaceuticals Inc.

Industry Sponsor

Trials

49

Recruited

11,700+

Founded

1993

Headquarters

San Diego, USA

Known For

Neurological Disorders

Top Products

Nuplazid (pimavanserin), Daybue (trofinetide)

Findings from Research

Prazosin is the only medication with established efficacy from multiple randomized controlled trials for treating sleep disturbances in PTSD, suggesting it may be crucial for improving overall symptoms of the disorder.

Other treatments like eszopiclone, risperidone, and olanzapine show promise as adjunct therapies, while common antidepressants and benzodiazepines appear ineffective, highlighting the importance of targeting sleep issues in PTSD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology for sleep disturbance in PTSD. Lipinska, G., Baldwin, DS., Thomas, KG.[2022]

In a 6-week double-blind, placebo-controlled trial with 37 participants suffering from trauma-related insomnia, suvorexant treatment showed significant improvements in PTSD and insomnia symptoms, although the strong placebo response made it difficult to determine the medication's specific effects.

Suvorexant was well tolerated, with only one participant dropping out due to side effects, and it was associated with increased REM sleep duration, which correlated with a reduction in PTSD symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of suvorexant for trauma-related insomnia. Mellman, TA., Birku, K., Sandhu, I., et al.[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]

The NAP Study is a large-scale clinical trial involving 1224 veterans with PTSD, comparing the efficacy of three insomnia medications (trazodone, eszopiclone, and gabapentin) against a placebo over 12 weeks, aiming to find effective treatments for PTSD-related insomnia.

The study features an adaptive design that allows for real-time adjustments based on interim results, potentially enhancing the statistical power of the remaining treatment comparisons and guiding future research on biomarkers for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016. Krystal, JH., Chow, B., Vessicchio, J., et al.[2022]

Pimavanserin, a selective 5-HT2A inverse agonist, was tested in a rat model of PTSD and showed significant potential to reduce anxiety and stress-related symptoms, particularly in female rats exposed to stress.

The study confirmed that doses of pimavanserin effectively blocked 5-HT2A receptor activity without causing adverse effects, indicating its safety and targeted mechanism of action in alleviating PTSD-like symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin reverses multiple measures of anxiety in a rodent model of post-traumatic stress disorder. Malin, DH., Tsai, PH., Campbell, JR., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacology for sleep disturbance in PTSD. [2022]

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

Evaluation of suvorexant for trauma-related insomnia. [2023]

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

Pimavanserin: First Global Approval. [2022]

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

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Pimavanserin reverses multiple measures of anxiety in a rodent model of post-traumatic stress disorder. [2023]