Trial Evaluating the Efficacy of Pimavanserin, a Selective Serotonin 5-HydroxyTryptamine-2A (5HT2A) Inverse Agonist, to Treat Impulse Control Disorders in Parkinson's Disease.

NCT06754553 | Not Yet Recruiting

• 1 other identifier: 9552
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 16

Brief Summary

There is no consensus on the treatment of Impulse Control Disorder (ICD) in Parkinson Disease (PD) though it is recommended to reduce the dosage of dopamine agonists (DA). Reduction of DA frequently leads to a worsening of motor signs (parkinsonism or dyskinesias due to the concomitant increase of levodopa doses) and non-motor signs with the appearance of a DA withdrawal syndrome (DAWS). Chronic stimulation of the sub-thalamic nuclei may reduce ICD but is restricted to a minority of patients and cases of new-onset ICD symptoms post stimulation have been reported. The benefit of amantadine in pathological gambling is controversial and the efficacy of clozapine has been reported in a few cases but with serious safety limitations. Very recently, naltrexone did not significantly improve ICD. Thus, an efficacious and safe treatment of ICD in PD remains an unmet need for clinical practice. Recently, it has been reported that pimavanserin, a selective serotonin 5-HT2A inverse agonist with a satisfactory safety profile without motor side effects, was efficient in improving psychosis, insomnia and day-time sleep in PD. Pimavanserin, marketed under the tradename NUPLAZID® was approved in 2016 by the U.S. Food and Drug Administration (FDA) for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. The link between serotonin and ICD has been well established, since the enhancement of 5HT2A receptors stimulation is associated to ICD, since serotonin modulates mesolimbic dopaminergic reward system transmission and given that serotonin neurotransmission is increased during chronic intake of dopamine agonist such as pramipexole which is well-known to induce ICD in PD patients. Thus, there is a large body of evidence suggesting that the decrease of the 5HT2A activity could be efficient in reducing ICD in PD. This further supports the concept of testing the efficacy of pimavanserin (a selective 5HT2A inverse agonist) for treating ICD in PD. Our aim is to conduct a study evaluating the efficacy and safety of pimavanserin on ICD in PD.

Conditions

Parkinson Disease

Keywords

Pimavanserin; Impulse Control Disorder; Serotoninergic 5-HT2A inverse agonist; Dopamine agonist

Outcome Measures

Primary Outcomes (1)

• Change in ICD (Impulsive Control Disorders) severity after 8 weeks of treatment evaluated by QUestionnaire for Impulse-compulsive disorder in Parkinson's disease Rating Scale (QUIP-RS).

  The primary endpoint of this study will be assessed in both arms using the total form of QUIP-RS. QUIP-RS has 4 primary questions (pertaining to commonly reported thoughts, urges/desires, and behaviors associated with ICDs), each applied to the 4 ICDs (compulsive gambling, buying, eating, and sexual behavior) and 3 related disorders (medication use, punding, and hobbyism). It uses a 5-point Likert scale (score 0-4 for each question) to gauge the frequency of behaviors. Scores for each ICD and related disorder range from 0 to 16 and the total QUIP-RS score for all ICDs and related disorders combined ranges from 0 to 112, with a higher score indicating greater severity (ie, frequency) of symptoms.

  at day 0 and week 8

Secondary Outcomes (11)

• Change SCale for Outcomes in Parkinson's disease - Sleep (SCOPA-SLEEP) score after 4 and 8 weeks of treatment

  At day 0, week 4 and week 8

• Change SCale for Outcomes in Parkinson's disease - Sleep (Insomnia severity index) score after 4 and 8 weeks of treatment

  At day 0, week 4 and week 8

• Change SCale for Outcomes in Parkinson's disease - Sleep (PDSS-2: Parkinson Disease Sleep Scale-2) score after 4 and 8 weeks of treatment

  At day 0, week 4 and week 8

• Change in Movement Disorders Society-sponsored Unified Parkinson's Disease Rating scale (MDS-UPDRS) scores after 4 and 8 weeks of treatment

  At day 0, week 4 and week 8

• Change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores after 4 and 8 weeks of treatment

  At day 0, week 4 and week 8

Study Arms (2)

Experimental: PIMAVANSERIN

In this arm, each patient took orally, once daily 2 tablets of active drug pimavanserin of 17mg each during the 8-weeks treatment period.

Behavioral: Assessment of severity of ICD (impulse control disorders); Behavioral: Assessment of motor and non-motors symptoms of PD Evaluation of hyper- and hypodopaminergic behaviors; Behavioral: Assessment of quality of life; Behavioral: Assessment of depression; Behavioral: Assessment of cognition; Behavioral: Assessment of severity of Parkinson Disease; Procedure: Cardiac monitoring

Placebo

In this arm, each patient took orally, once daily, 2 tablets of matching placebo (containing all of the same excipients except for the active compound) during the 8-weeks treatment period.

Behavioral: Assessment of severity of ICD (impulse control disorders); Behavioral: Assessment of motor and non-motors symptoms of PD Evaluation of hyper- and hypodopaminergic behaviors; Behavioral: Assessment of quality of life; Behavioral: Assessment of depression; Behavioral: Assessment of cognition; Behavioral: Assessment of severity of Parkinson Disease; Procedure: Cardiac monitoring

Interventions

Assessment of severity of ICD (impulse control disorders) BEHAVIORAL

Questionnaire for impulsive-compulsive disorders in Parkinson's disease rating scale (QUIP-RS) administered at day 0, day 28 (Week 4) and day 56 (Week 8)

Experimental: PIMAVANSERIN; Placebo

Assessment of motor and non-motors symptoms of PD Evaluation of hyper- and hypodopaminergic behaviors BEHAVIORAL

Hyper- and hypodopaminergic behaviors (Ardouin's scale); Movement disorders society sponsored unified Parkinson's disease rating scale (MDS-UPDR), and daytime and night time sleep by scale for outcomes in Parkinson's disease SLEEP (SCOPA-SLEEP, ISI, PDSS-2) administered at day 0, day 28 (Week 4) and day 56 (Week 8)

Experimental: PIMAVANSERIN; Placebo

Assessment of quality of life BEHAVIORAL

Parkinson's Disease questionnaire (PDQ-39) administered at day 0, day 28 (Week 4) and day 56 (Week 8)

Experimental: PIMAVANSERIN; Placebo

Assessment of depression BEHAVIORAL

Montgomery-Åsberg Depression Rating Scale (MADRS) administered at day 0 and day 56 (week 8)

Experimental: PIMAVANSERIN; Placebo

Assessment of cognition BEHAVIORAL

Cognitive state of patients by Montreal Cognitive Assessment (MOCA) assessed at day 0

Experimental: PIMAVANSERIN; Placebo

Assessment of severity of Parkinson Disease BEHAVIORAL

Clinical Global Impression Severity scale (CGIS) administered at day 0 , day 7, day 14, day 28, day 42 and day 56 (week 8) and day 112 (Week 16)

Experimental: PIMAVANSERIN; Placebo

Cardiac monitoring PROCEDURE

Electrocardiogram realized at day 0, 28 and 56.

Experimental: PIMAVANSERIN; Placebo

Eligibility Criteria

• Age: 35 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Participants randomized in the PIMPARK study (PHRC 2015-HUS 6398)

You may qualify if:

• Patient with PD according to the UKPDSBB criteria for at least 1 year before randomization
• Patient, man or woman, aged from 35 to 75 years old
• Patient with moderately severe ICD assessed by QUIP-RS (each item being rated 0-16) defined as:
• a combined ICD total score (defined as the sum of the 4 ICD sub-scores (pathological gambling + buying + hypersexuality + eating)) superior or equal to 10 or, at least one of the 4 ICD sub-scores in the following range:
• "pathological gambling" sub-score from 6 to 12 (included), "buying" sub-score from 8 to 12 (included), "hypersexuality" sub-score from 8 to 12 (included), "eating" sub-score from 7 to 12 (included) (Weintraub et al., 2012). The use of "lower" margins will guarantee that the patient experiences behavioral disturbances severe enough to justify pimavanserin treatment. On the other hand, the use of "upper" margins will guarantee that the patients included in the trial will not suffer from ICD severe enough to question ethically the use of placebo during the 8 weeks of the treatment. Eligibility of patients with QUIP-RS sub-scores above 12 will be assessed upon investigator's request by an adjudication committee composed by independent experts external to the study
• ICD onset after PD onset and after initiation of dopaminergic drugs
• Patient treated by dopaminergic drugs for at least 3 months before randomization in the PIMPARK study
• Patient treated with a stable regimen of levodopa, dopamine agonists, COMT and MAOB inhibitors, amantadine, anticholinergic, antidepressant and benzodiazepine for at least 1 month before the randomization and be willing to remain on the same doses throughout the course of their participation in the trial (Papay et al., 2014)
• Patient with health insurance
• Patient/ guardian / curator who sign the written informed consent for the PIMPARK study
• For women of childbearing potential, use of an effective contraception method for at least 1 month prior to randomization in the PIMPARK study until 8 weeks after the last dose of study drug administration.
• Having participated in the PHRC N 2015 - HUS N°6398 study (PIMPARK study) during the period from 23/10/2020 to 17/06/2024.
• Not objecting, after information, to the reuse of its data from the study PHRC N 2015 - HUS N°6398 for the purposes of this research.

You may not qualify if:

• Patient suffering from another parkinsonian syndrome (multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, corticobasal degeneration)
• Patient who have a known hypersensitivity to the study treatment, based on known allergies to drugs of the same class
• Stroke, uncontrolled serious medical illness, myocardial infarction, congestive heart failure, cardiac function disorders, within 6 months before randomization
• Patient with history of long QT syndrome
• Patient treated with antipsychotic drugs during the last three months before randomization in the PIMPARK study
• Patient treated with concomitant medication leading to torsade de pointes (TdP) without discontinuation ≥ 5 half-lives before randomization (please refer to medications list with known risks of TdP on appendix XVII.5.10 and check website https://crediblemeds.org/index.php/tools/ for the most up-to-date information)
• ≤ K+ ≤ 5 mmol/L 135 ≤ Na+ ≤ 145 mmol/L 2,20 ≤ Ca2+ ≤ 2,60 mmol/L
• Patient treated with a strong or moderate CYP3A4 inducer: carbamazepine, rifampicin, phenytoin, modafinil, efavirenz or a strong inhibitor of CYP3A4: azole antifungals, protease inhibitors, macrolids, without discontinuation ≥ 5 half-lives before randomization
• History of DBS within the past year before randomization, or change in stimulation parameters less than one month prior to randomization Hematologic or solid malignancy diagnosis within 5 years prior to randomization.
• Clinically significant hepatic impairment
• Concurrent participation in another research involving a drug or medical device
• Patient with language barriers precluding adequate understanding or co-operation or who, in the opinion of the investigator, should not participate in the trial
• Treatment with an investigational treatment within 30 days prior to randomization
• Woman pregnant, nursing or of childbearing potential age without effective contraception methods or intends to become pregnant.

Sponsors & Collaborators

• University Hospital, Strasbourg, France: lead
• NS-PARK Network: collaborator
• EUCLID Clinical Trial Platform: collaborator
• F-CRIN: collaborator

Study Sites (16)

Service de Neurologie et Centre d'Investigation Clinique CHRU de Besançon,

Besançon, 25000, France

Location

SERVICE DE NEUROLOGIE Unité Mouvement anormaux Centre expert Parkinson (centre coordinateur interrégional pour la région Sud-Est) Service de neurologie C Hôpitaux Universitaires de Lyon Hôpital Neurologique Pierre Wertheimer

Bron, 69677, France

Location

SERVICE DE NEUROLOGIE Unité Mouvement anormaux Centre expert Parkinson (région Sud-Est) Hôpitaux Universitaires de Clermont-Ferrand Hôpital Gabriel Montpied

Clermont-Ferrand, 63003, France

Location

SERVICE DE NEUROLOGIE Pathologies du mouvement Centre expert Parkinson (région Ile-de-France) Hôpital Henri Mondor

Créteil, 94010, France

Location

SERVICE DE NEUROLOGIE Pathologies du mouvement Centre expert Parkinson (région Sud-Est) CHU de Grenoble Alpes

Grenoble, 38043, France

Location

SERVICE DE NEUROLOGIE Unité Mouvement anormaux Centre expert Parkinson (centre de coordination pour la région Nord-Ouest) Hôpitaux Universitaires de Lille Hôpital Roger Salengro

Lille, 59037, France

Location

SERVICE DE NEUROLOGIE Pathologies du mouvement Centre expert Parkinson (région Sud-Ouest) Hôpitaux Universitaires de Limoges

Limoges, 87042, France

Location

SERVICE DE NEUROLOGIE Unité Mouvement anormaux Centre expert Parkinson (centre de coordination pour la région Sud Méditerranée) Hôpitaux Universitaires de Marseille Hôpital La Timone

Marseille, 13385, France

Location

SERVICE DE NEUROLOGIE Pathologies du mouvement Centre expert Parkinson (centre de coordination pour la région Ouest) Centre d'investigation clinique Hôpitaux Universitaires de Nantes

Nantes, 44093, France

Location

SERVICE DE NEUROLOGIE Centre expert Parkinson (centre de coordination pour la région Ile-de-France) Hôpital de la Pitié-Salpêtrière

Paris, 75651, France

Location

CIC Hôpitaux Universitaires de Poitiers

Poitiers, 86021, France

Location

Service de neurologie, Hôpitaux Universitaires de REIMS

Reims, 51 100, France

Location

SERVICE DE NEUROLOGIE Pathologies du mouvement Centre expert Parkinson (région Ouest) Hôpitaux Universitaires de Rennes-Hôpital Pontchaillou

Rennes, 35033, France

Location

SERVICE DE NEUROLOGIE Pathologies du mouvement Centre expert Parkinson (région Nord-Ouest) Hôpitaux Universitaires de Rouen Hôpital Charles Nicolle

Rouen, 76031, France

Location

SERVICE DE NEUROLOGIE Unité Mouvement anormaux Centre expert Parkinson (centre de coordination pour la région Est) Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre

Strasbourg, 67098, France

Location

SERVICE DE NEUROLOGIE Unité Mouvement anormaux Centre expert Parkinson/Centre d'Investigation Clinique -Hôpital Pierre-Paul Riquet

Toulouse, 31059, France

Location

MeSH Terms

Conditions

Parkinson Disease; Disruptive, Impulse Control, and Conduct Disorders

Interventions

Mental Status and Dementia Tests

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Mental Disorders

Intervention Hierarchy (Ancestors)

Neuropsychological Tests; Psychological Tests; Behavioral Disciplines and Activities

Central Study Contacts

Mathieu ANHEIM, MD PhD

CONTACT

+33 3 88 12 85 35; mathieu.anheim@chru-strasbourg.fr

Olivier RASCOL, MD PhD

CONTACT

+33 5 61 14 59 62; olivier.rascol@univ-tlse3.fr

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 30, 2024
• First Posted: January 1, 2025
• Study Start: February 1, 2025
• Primary Completion: February 1, 2026
• Study Completion: February 1, 2026
• Last Updated: January 1, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (16)