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

NCT03947216 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: 63982016-001229-15
• Study Type: interventional
• Target: 117
• 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. This clinical trial is conducted with the support of the French NS-Park/FCRIN (French Clinical Research Infrastructure Network) network.

Conditions

Parkinson Disease

Keywords

impulse control disorders; pimavanserin; Serotoninergic 5-HT2A inverse agonist; Dopamine agonist; Behavior

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 (10)

• 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

Other Outcomes (1)

• Total number of adverse events and serious adverse events

  At week 16

Study Arms (2)

PIMAVANSERIN

EXPERIMENTAL

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

Drug: Active drug: pimavanserin 17mg (2 strength tablets); 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: Blood analysis; Procedure: Cardiac monitoring

PLACEBO

PLACEBO COMPARATOR

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

Drug: Placebo: 2 tablets containing same excipients except active compound; 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: Blood analysis; Procedure: Cardiac monitoring

Interventions

Active drug: pimavanserin 17mg (2 strength tablets) DRUG

Pimavanserin 17mg (2 strength tablets) will be taken orally daily from day 1 to Visit 4 (Week 8)

PIMAVANSERIN

Assessment of severity of ICD (impulse control disorders) BEHAVIORAL

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

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) will be administrated at day 0, day 28 (Week 4) and day 56 (Week 8)

PIMAVANSERIN; PLACEBO

Assessment of quality of life BEHAVIORAL

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

PIMAVANSERIN; PLACEBO

Assessment of depression BEHAVIORAL

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

PIMAVANSERIN; PLACEBO

Assessment of cognition BEHAVIORAL

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

PIMAVANSERIN; PLACEBO

Assessment of severity of Parkinson Disease BEHAVIORAL

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

PIMAVANSERIN; PLACEBO

Blood analysis PROCEDURE

Blood sample will be collected for analyse of safety (blood count/liver and kidney functions, electrolytes) at day 0 and day 56

PIMAVANSERIN; PLACEBO

Cardiac monitoring PROCEDURE

Electrocardiogram will be realized at day 0, 28 and 56.

PIMAVANSERIN; PLACEBO

Placebo: 2 tablets containing same excipients except active compound DRUG

Placebo (2 strength tablets) will be taken orally daily from day 1 to Visit 4 (Week 8)

PLACEBO

Eligibility Criteria

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

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 (cf IX.3 Adjudication Committee).
• ICD onset after PD onset and after initiation of dopaminergic drugs
• Patient treated by dopaminergic drugs for at least 3 months before randomization
• 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 women of childbearing potential, use of an effective contraception method\* for at least 1 month prior to randomization until 8 weeks after the last dose of study drug administration. Women who do not have an effective contraception\* must : have had her last natural menstruation ≥24 months prior to the selection visit, or have been surgically sterilized prior to the selection visit, or have had a hysterectomy prior to the selection visit.

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
• 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
• Patient treated with medicinal plants interacting with CYP3A4 without discontinuation ≥ 5 half-lives before randomization (Echinacea (E.pupurea, E.angustifolia and E.pallida), Piperina, Artemisia, St. John's Wort and Ginkgo
• 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.
• \[Note: Subjects with a history of localized skin cancer, basal cell or squamous cell carcinoma, may be enrolled in the study as long as they are cancer free prior to randomization. Subjects with other localized cancers (without metastatic spread) who have previously completed their course of treatment more than 5 years prior to randomization, are not currently receiving treatment and have been in remission may be enrolled only if, in the opinion of the Investigator, there is no expectation for recurrence or further cancer treatment during the study period. Antihormonal therapy (e.g., tamoxifen) is allowed if the subject's cancer is in remission and the subject is on stable maintenance therapy to reduce their risk of recurrence.\]
• 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

Sponsors & Collaborators

• University Hospital, Strasbourg, France: lead
• NS-PARK: collaborator
• EUCLID Clinical Trial Platform: collaborator
• F-CRIN: collaborator
• ACADIA Pharmaceuticals Inc.: collaborator

Study Sites (16)

Service de Neurologie and CIC -CHU Besançon

Besançon, France

Location

SERVICE DE NEUROLOGIE C, Unité mouvement anormaux/Centre expert Parkinson, CHU de Lyon, Hopital neurologique Pierre Wertheimer

Bron, 69677, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson CHU Clermont-Ferrand, Hopital Gabriel Montpied

Clermont-Ferrand, 63003, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson, Hopital Henri Mondor

Créteil, 94010, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson, CHU de Grenoble Alpes

Grenoble, 38043, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvement Anormaux/Centre expert Parkinson, CHU de Lille, Hopital Roger Salengro

Lille, 59037, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson, CHU de Limoges

Limoges, 87042, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvement Anormaux/Centre expert Parkinson, Hopital de la Timone

Marseille, 13385, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson, CIC, CHU de Nantes, Hopital Laennec

Nantes, 44093, France

Location

SERVICE DE NEUROLOGIE Centre Expert Parkinson Hopital de la Pitié-Salpêtrière

Paris, 75651, France

Location

Centre d'Inverstigation Clinique, CHU de Poitiers

Poitiers, 86021, France

Location

SERVICE DE NEUROLOGIE, CHU de REIMS

Reims, 51100, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson, CHU de Rennes, Hopital Pontchaillou

Rennes, 35033, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson, CHU de Rouen, Hopital Charles Nicolle

Rouen, 76031, France

Location

SERVICE DE NEUROLOGIE Unité de Mouvements Anormaux/Centre expert Parkinson, CHU de Strasbourg, Hopital de Hautepierre

Strasbourg, 67098, France

Location

SERVICE DE NEUROLOGIE, Unité Mouvements Anormaux/Centre expert Parkinson, CIC, CHU de Toulouse, Hopital Pierre-Paul Riquet

Toulouse, 31059, France

Location

MeSH Terms

Conditions

Parkinson Disease; Disruptive, Impulse Control, and Conduct Disorders; Behavior

Interventions

Mental Status and Dementia Tests; Hematologic 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; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Mathieu ANHEIM, MD

  CHRU Strasbourg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2019
• First Posted: May 13, 2019
• Study Start: October 23, 2020
• Primary Completion: April 23, 2024
• Study Completion: June 17, 2024
• Last Updated: March 16, 2026

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (16)