Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia

Study Overview
=================
Brief Summary
-----------------
Mesdopetam (IRL790) is an experimental small molecule compound with psychomotor stabilizing properties. The primary target is the dopamine D3 receptor, a target implicated in the generation of levodopa-induced dyskinesia, a side-effect frequently occurring with long-term levodopa treatment in patients with Parkinson's disease. In experimental animals mesdopetam potently reduced levodopa-induced involuntary movement without impairing the antiparkinsonian effect of levodopa. The primary purpose of the trial is to investigate whether mesdopetam given as adjunctive treatment can reduce levodopa induced dyskinesia in patients with Parkinson's disease. The trial will also help to establish the most optimal dosing of the compound.

Detailed Description
-----------------
METHODOLOGY: This is a multicentre study where 74 patients with Parkinson's disease exhibiting levodopa induced dyskinesia will be randomised to receive study drug or placebo. Thirty seven patients will be randomised to mesdopetam and 37 patients to placebo (1:1 randomisation). Patients will be screened for eligibility according to inclusion/exclusion criteria within four weeks of initiation of study treatment (Screening visit). An outpatient study with the patients taking the study drug for four weeks at home. Mesdopetam will be taken twice daily (b.i.d.) as adjunctive treatment to the patients' regular and stable antiparkinsonian medication. The first two weeks of treatment will allow for per patient titration of study medication to the highest tolerated predefined dose, after which patients will continue on this highest tolerated dose for an additional two weeks. Changes in disease state and dyskinesia will be measured using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Unified Dyskinesia Rating Scale (UDysRS); furthermore, patients will administer two 24-hour diaries on run-in and on the fourth week of dosing to assess daily movements. Pharmacokinetic (PK) samples will be collected for the determination of concentrations of mesdopetam and its metabolites IRL902 and IRL872 in plasma. They will be collected before and after IMP administration at two visits. A Follow-up Visit will be performed for all patients five to eight days after last administration of IMP.

Official Title
-----------------
A Randomized, Placebo-controlled, Phase IIa Study Evaluating the Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: Mesdopetam (IRL790)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female ≥18 and ≤79 years of age. Signed a current Ethics Committee approved informed consent form. Parkinson's disease, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria. Waking day dyskinesia of ≥25% determined as a score of ≥2 as per Question 4.1 of the MDS-UPDRS. On a stable regimen of antiparkinson medications for at least 30 days prior to screening, including a levodopa preparation administered not less than three times daily and willing to continue the same doses and regimens during study participation. Rescue medication such as Madopar dispersable and Apomorphine injections are allowed. Taking a maximum of eight regular levodopa intakes per day, excluding bedtime and night time levodopa. Any other current and allowed prescription/non-prescription medications and/or nutritional supplements taken regularly must have been at a stable dose and regimen for at least 30 days prior to screening and the patient must be willing to continue the same doses and regimens during study participation (this criterion does not apply to medications that are being taken pre-study only on an as-needed basis). Patient must be willing and able to avoid direct exposure to sunlight from day 1 to day 28. Able to complete at least one valid 24-hour patient diary at Visit 1. Exclusion Criteria: History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain stimulation). Treatment with pump delivered antiparkinsonian therapy (i.e. subcutaneous apomorphine or levodopa/carbidopa intestinal infusion). History of seizures within two years prior to screening. History of stroke or transient ischemic attack (TIA) within two years prior to screening. History of cancer within five years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localised bladder cancer, non-metastatic prostate cancer or in situ cervical cancer. Presence of cognitive impairment, as evidenced by a Mini-Mental Status Examination (MMSE) score of less than 24 during screening. A Hoehn and Yahr score of five when off as per Question 3.18 of the MDS-UPDRS, assessed during screening. Any history of a significant heart condition or cardiac arrhythmias within the past 5 years, any repolarisation deficits or any other clinically significant abnormal ECG as judged by the Investigator Severe or ongoing unstable medical condition including a history of poorly controlled diabetes; obesity associated with metabolic syndrome; uncontrolled hypertension; cerebrovascular disease, or any form of clinically significant cardiac disease; clinically significant symptomatic orthostatic hypotension; clinically significant hepatic disease, renal failure or abnormal renal function. Any history of a neurological other than Parkinson's disease or a psychiatric disorder, including history of DSM IV diagnosed major depression or psychosis. Patients with illusions or hallucinations with no loss of insight will be eligible. Patients with mild depression who are well controlled on a stable dose of an antidepressant medication for at least 4 weeks before screening will be eligible. Enrolment in any other clinical study involving medication, medical devices or surgical procedures, current or within three months prior to screening visit, or previous participation in the present study. Patients enrolled in non-interventional clinical trials will be eligible. Drug and/or alcohol abuse. History of severe drug allergy or hypersensitivity. If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose. Patients unwilling to use two forms of contraception 90 days for men and 30 days for women after last IMP dose Any planned major surgery within the duration of the study. Any other condition or symptoms preventing the patient from entering the study, according to the Investigator's judgement.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind, placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesdopetam (IRL790)<br>Capsule 2.5 mg, oral administration | Drug: Mesdopetam (IRL790)<br>* Mesdopetam (IRL790) capsule<br>* Other names: IRL790;|
| Placebo Comparator: Placebo<br>Identical capsule, oral administration | Drug: Mesdopetam (IRL790)<br>* Mesdopetam (IRL790) capsule<br>* Other names: IRL790;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unified Dyskinesia Rating Scale (UDysRS) | The change from baseline to day 28 of treatment (Visit 4) in the sum of the items comprising the Unified Dyskinesia Rating Scale (UDysRS). The Unified Dyskinesia Rating Scale (UDysRS) is administered to assess dyskinesia. The scoring range is 0-104, where higher score means more dyskinesia. | Baseline and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, Question 4.1 and 4.2 | Change in MDS-UPDRS sum score of questions 4.1 (Time spent with dyskinesias) and 4.2 (Functional impact of dyskinesias) in part IV from baseline to visit 4. Minimum score is 0 and maximum score is 8. A higher score means more dyskinesia. | Baseline and 4 weeks | 
| Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part II and III | Change in MDS-UPDRS sum score of parts II+III (Motor aspects of Experiences of Daily living + Motor Examination) from baseline to visit 4. Minimum value is 0 and maximum value is 124. Higher score mean a worse outcome. | Baseline and 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Levodopa induced dyskinesia