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.

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

Interventions

DRUG

Active drug: pimavanserin 17mg (2 strength tablets)

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

DRUG

Placebo: 2 tablets containing same excipients except active compound

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

BEHAVIORAL

Assessment of severity of ICD (impulse control disorders)

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)

BEHAVIORAL

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

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)

BEHAVIORAL

Assessment of quality of life

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

BEHAVIORAL

Assessment of depression

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

BEHAVIORAL

Assessment of cognition

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

BEHAVIORAL

Assessment of severity of Parkinson Disease

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)

PROCEDURE

Blood analysis

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

PROCEDURE

Cardiac monitoring

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

Sponsors & Collaborators

• NS-PARK

  collaborator UNKNOWN

• EUCLID Clinical Trial Platform

  collaborator OTHER

• F-CRIN

  collaborator UNKNOWN

• ACADIA Pharmaceuticals Inc.

  collaborator INDUSTRY

• University Hospital, Strasbourg, France

  lead OTHER

Principal Investigators

• Mathieu ANHEIM, MD · CHRU Strasbourg

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

35 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-10-23

Primary Completion

2024-04-23

Completion

2024-06-17

FDA Drug

Yes

Countries

• France

Study Locations