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.

Prior treatment

• Stroke, uncontrolled serious medical illness, myocardial infarction, congestive heart failure, cardiac function disorders, within 6 months before randomization
• 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)
• 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.
  • \[Note: Subjects with a history of localized skin cancer, basal cell or squamous cell carcinoma, may be enrolled in the study as long as they are cancer free prior to randomization. Subjects with other localized cancers (without metastatic spread) who have previously completed their course of treatment more than 5 years prior to randomization, are not currently receiving treatment and have been in remission may be enrolled only if, in the opinion of the Investigator, there is no expectation for recurrence or further cancer treatment during the study period. Antihormonal therapy (e.g., tamoxifen) is allowed if the subject's cancer is in remission and the subject is on stable maintenance therapy to reduce their risk of recurrence.\]
• Patient suffering from severe renal impairment define as CrCL\<30 mL/min, Cockcroft-Gault at inclusion visit or assessed no later than 8 days before randomization
• Concurrent participation in another research involving a drug or medical device
• Treatment with an investigational treatment within 30 days prior to randomization

Other illness

• 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
• Patient with Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005) score \< 20 (to exclude patients likely with dementia) at inclusion visit (Papay et al., 2014).
• Clinically significant hepatic impairment

Lab values

• Patient with history of long QT syndrome
• Patient with hydro-electrolytics troubles, particularly hypokaliemia or hypocalcemia not corrected, at inclusion visit or assessed no later than 8 days before randomization. To be eligible, the patient's electrolyte values should be within the following limits:
  • 3.5 ≤ K+ ≤ 5 mmol/L 135 ≤ Na+ ≤ 145 mmol/L 2,20 ≤ Ca2+ ≤ 2,60 mmol/L

Age

• Woman pregnant, nursing or of childbearing potential age without effective contraception methods\* or intends to become pregnant.
  • an effective contraception method is defined as implants, oral oestro-progestative contraceptives or progestative which inhibit ovulation contraceptives (e.g, desogestrel), or double barrier method (condom plus spermicide or diaphragm plus spermicide) or levonorgestrel intrauterine devices, or vasectomized partner (confirmed with two negative spermograms).

Other

• Patient with long QTcB detected with ECG at inclusion visit (\> 450 ms)
• Patient suffering from severe depression or marked suicidal thoughts (score \> 3 on the suicidal thoughts item of the MADRS) at inclusion visit (Papay et al., 2014)
• Patient with language barriers precluding adequate understanding or co-operation or who, in the opinion of the investigator, should not participate in the trial

• 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.