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.

Study of Pimavanserin Efficacy for the Treatment of Impulse Control Disorders in Parkinson's Disease

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.

Inclusion Criteria:

1. Patient with PD according to the UKPDSBB criteria for at least 1 year before randomization

2. Patient, man or woman, aged from 35 to 75 years old

3. 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:

     1. "pathological gambling" sub-score from 6 to 12 (included),
     2. "buying" sub-score from 8 to 12 (included),
     3. "hypersexuality" sub-score from 8 to 12 (included),
     4. "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).

4. ICD onset after PD onset and after initiation of dopaminergic drugs

5. Patient treated by dopaminergic drugs for at least 3 months before randomization

6. 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)

7. Patient with health insurance

8. Patient/ guardian / curator who sign the written informed consent

9. 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.

Exclusion Criteria:

1. Patient suffering from another parkinsonian syndrome (multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, corticobasal degeneration)

2. Patient who have a known hypersensitivity to the study treatment, based on known allergies to drugs of the same class

3. Stroke, uncontrolled serious medical illness, myocardial infarction, congestive heart failure, cardiac function disorders, within 6 months before randomization

4. Patient with history of long QT syndrome

5. Patient with long QTcB detected with ECG at inclusion visit (> 450 ms)

6. Patient treated with antipsychotic drugs during the last three months before randomization

7. 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)

8. 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

9. 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

10. 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

11. 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).

12. 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)

13. History of DBS within the past year before randomization, or change in stimulation parameters less than one month prior to randomization

14. 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.]

15. 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

16. Clinically significant hepatic impairment

17. Concurrent participation in another research involving a drug or medical device

18. Patient with language barriers precluding adequate understanding or co-operation or who, in the opinion of the investigator, should not participate in the trial

19. Treatment with an investigational treatment within 30 days prior to randomization

20. 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).