Clinical trial NCT04435431: A Clinical Study of Mesdopetam in Patients With Parkinson's Disease Experiencing Levodopa Induced Dyskinesia
Official title: A Randomized, Double-blind, Placebo-controlled Phase IIB Study Evaluating the Efficacy of Mesdopetam on Daily ON-time Without Troublesome Dyskinesia in Patients With Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson Disease
Lead sponsor: Integrative Research Laboratories AB
Sponsor class: INDUSTRY
First posted: 2020-06-17
Enrollment: 155
Sex: ALL
Minimum age (years): 30
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 2b study investigating the efficacy and safety of mesdopetam as adjunct therapy on daily ON-time without troublesome dyskinesia in patients with Parkinson disease. Mesdopetam is taken for 84 days.

Detailed description: At the screening visit consenting patients will be screened for eligibility according to study specific inclusion/exclusion criteria within 8 weeks before start of Investigational Medicinal Product (IMP) administration. A diary concordance training will be performed and following the screening visit the patient will be asked to self-administer three 24-hour home diaries and to bring the completed diaries to the baseline visit for assessment prior randomization.

At the baseline visit, patients will be randomized to receive one of three doses of mesdopetam (dose 1, dose 2 and dose 3) or placebo b.i.d.

During the first week a dose run-in phase will take place, where all patients allocated to mesdopetam will receive a run-in dose of mesdopetam twice daily and patients allocated to placebo will receive placebo twice daily. At Visit 2, patients will receive mesdopetam dose 1, dose 2 or dose 3 or placebo b.i.d., as randomized and continue the same dose for the rest of the treatment period until end of treatment (EOT). Dose reductions are restricted and the dose can only be reduced once. Dose reductions are permitted from visit 2 (day 9) until visit 3 (day 28), where after the dose should be kept stable until EOT.

The treatment allocation will be double-blind, i.e. it will not be disclosed to the patients, the site staff or the Sponsor.

During the treatment period, changes in disease state and ON phase dyskinesia will be assessed using the Movement Disorder Society revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the modified Unified Dyskinesia Rating Scale (UDysRS), i.e. parts 1, 3 and 4, and Clinician's Global Impression of Severity (CGI-S). Furthermore, patients will self-administer three 24-hour home diaries prior to visit 3 (week 4), visit 4 (week 8) and visit 5 (week 12) to assess daily motor function.

Blood samples for pharmacokinetic (PK) analysis will be collected at visit 4 (week 8) and visit 5 (week 12).

Visit 6 (follow-up) will be performed for all patients, including any patients that discontinue the IMP early, 5-8 days after last administration of IMP.

Eligibility criteria: Inclusion Criteria:

1. Male or female ≥30 and ≤79 years of age at the time of screening.
2. Signed a current Ethics Committee approved informed consent form (ICF).
3. PD, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria.
4. Minimal amount of 2 hours of levodopa-induced daily "ON-time with troublesome dyskinesia" during waking hours
5. Functional impact of dyskinesias determined as a score of ≥2 as per Question 4.2 of the MDS-UPDRS.
6. On a stable regimen of antiparkinson medications for at least 30 days prior to first home diary completion which must include a levodopa preparation administered 3-8 times/day (excluding nighttime levodopa) and willing to continue the same doses and regimens during study participation. Rescue medications such as Madopar dispersable and Apomorphine injections are allowed if prescribed PRN prior to study entry.
7. 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 first home diary completion 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).
8. Able to complete 24-hour patient home diaries of which two valid diaries must be presented at visit 1.

Exclusion Criteria:

1. History of neurosurgical intervention related to PD (e.g. deep brain stimulation).
2. Treatment with pump delivered antiparkinsonian therapy (i.e. subcutaneous apomorphine or levodopa/carbidopa intestinal infusion).
3. History of seizures within two years prior to screening.
4. History of stroke or transient ischemic attack (TIA) within two years prior to screening.
5. History of cancer within five years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localized bladder cancer, non metastatic prostate cancer or in situ cervical cancer.
6. Presence of cognitive impairment, as evidenced by a Mini-Mental State Examination (MMSE) score of less than 24 during screening.
7. A Hoehn and Yahr stage of 5.
8. Ongoing treatment with amantadine at time of screening or within 6 weeks prior first home diary completion.
9. Treatment with Inbrija (levodopa inhalation powder) at time of screening or within 4 weeks prior first home diary completion.
10. 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.
11. 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 (a fall and/or a discomfort); clinically significant hepatic disease, severe renal impairment, i.e. creatinine clearance \<30 mL/min (stage IV or V).
12. Any history of a neurological disorder other than PD or a psychiatric disorder, including history of Diagnostic and Statistical Manual of Mental Disorders (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.
13. 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.
14. Drug and/or alcohol abuse.
15. History of severe drug allergy or hypersensitivity.
16. If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose.
17. Patients unwilling to use two forms of contraception (one of which being a barrier method (see Section 8.1) during the treatment period and 90 days for men and 30 days for women after last IMP dose.
18. Any planned major surgery within the duration of the study.
19. Any other condition or symptoms preventing the patient from entering the study, according to the Investigator's judgement.

Primary outcomes:
measure: Change in Average Daily Hours of ON-time Without Troublesome Dyskinesia With Mesdopetam Compared to Placebo as Assessed With 24-hour Patient Home Diaries From Baseline to End of Treatment.
timeFrame: Baseline to end of treatment (week 12)
Secondary outcomes:
measure: Change From Baseline in Mean Score of ON-phase Dyskinesia Assessed With the Sum Score of the Modified Unified Dyskinesia Rating Scale (UDysRS), Parts 1, 3 and 4, With Mesdopetam Compared to Placebo.
timeFrame: Baseline to end of treatment (week 12)
measure: Change From Baseline in Mean Score of Disability Associated With ON-phase Dyskinesia Assessed With the Sum Score of Parts 1b and 4 of the Unified Dyskinesia Rating Scale (UDysRS), With Mesdopetam Compared to Placebo.
timeFrame: Baseline to end of treatment (week 12)
measure: Change From Baseline in Mean Score of Motor Symptoms of PD Assessed With MDS-UPDRS Total Score of Part 2 (M-EDL) (With Mesdopetam Compared to Placebo)
timeFrame: Baseline to end of treatment (week 12)
measure: Change From Baseline in Average Daily Hours of OFF-time (With Mesdopetam Compared to Placebo).
timeFrame: Baseline to end of treatment (week 12)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Movement Disorders Center of Arizona
state: Arizona
city: Long Beach
country: United States
facility: Collaborative Neuroscience Research (CNS Research)
state: California
city: Palo Alto
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Silicon Valley
state: California
city: Colorado Springs
country: United States
facility: Colorado Springs Neurological Associates
state: Colorado
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Miami Gardens
country: United States
facility: Life Medical Research Group Corp
state: Florida
city: Miami
country: United States
facility: Avantis Clinical Research
state: Florida
city: Miami
country: United States
facility: Elias Research Associates (Allied Biomedical Research Institute)
state: Florida
city: Miami
country: United States
facility: Pharmax Research of South Florida, Inc.
state: Florida
city: Decatur
country: United States
facility: NeuroStudies.net, LLC
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky, Department of Neurology
state: Kentucky
city: Tulsa
country: United States
facility: The Movement Disorder Clinic of Oklahoma
state: Oklahoma
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
city: Lille
country: France
facility: Centre Hospitalier Regional Universitaire de Lille
city: Limoges
country: France
facility: CHU Dupuytren 1 - Neurologie
city: Nimes
country: France
facility: CHU Carémeau
city: Poitiers
country: France
facility: CHU de Poitiers
city: Rennes
country: France
facility: CHU Rennes-Pontchaillou
city: Rouen
country: France
facility: CHU Charles Nicolle; Service de Neurologie
city: Haifa
country: Israel
facility: Rambam Health Care Campus, Department of Neurology
city: Jerusalem
country: Israel
facility: Hadassah University Hospital-Ein Kerem, Department of Neurology
city: Petah Tikva
country: Israel
facility: Rabin Medical Centre - Beilinson Hospital, Department of Neurology
city: Ramat Gan
country: Israel
facility: The Chaim Sheba Medical Centre, Department of Neurology
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Centre; Movement Disorders Unit
city: Genova
country: Italy
facility: IRCCS - Ospedale "San Martino"
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Roma
country: Italy
facility: IRCCS San Raffaele Pisana
city: Roma
country: Italy
facility: Fondazione Policlinico Gemelli IRCCS
city: Salerno
country: Italy
facility: AOU San Giovanni di Dio e Ruggi d'Aragona, Clinica Neurologica
city: Bydgoszcz
country: Poland
facility: Centrum Medyczne Neuromed
city: Katowice
country: Poland
facility: Specjalistyczna Praktyka Lekarska
city: Kraków
country: Poland
facility: Centrum Medyczne PLEJADY
city: Kraków
country: Poland
facility: Specjalistyczne Gabinety Sp z o.o.
city: Kraków
country: Poland
facility: Krakowska Akademia Neurologii
city: Oświęcim
country: Poland
facility: Instytut Zdrowia
city: Siemianowice Śląskie
country: Poland
facility: Neuro-Care
city: Warsaw
country: Poland
facility: Next Stage sp.z o.o.
city: Warszawa
country: Poland
facility: Centrum Medyczne NeuroProtect
city: Zabrze
country: Poland
facility: ClinHouse Centrum Medyczne
city: Belgrade
country: Serbia
facility: Clinical Hospital Center Zvezdara, Clinical department of Neurology
city: Belgrade
country: Serbia
facility: University Clinical Center of Serbia, Clinic for Neurology
city: Kragujevac
country: Serbia
facility: University Clinical Center Kragujevac, Clinic for Neurology (Site 601)
city: Kragujevac
country: Serbia
facility: University Clinical Center Kragujevac, Clinic for Neurology (Site 602)
Study officials:
affiliation: Integrative Research Laboratories AB (IRLAB)
name: Joakim Tedroff
role: STUDY_DIRECTOR
References:
citation: Becanovic K, Vittoria de Donno M, Sousa VC, Tedroff J, Svenningsson P. Effects of a Novel Psychomotor Stabilizer, IRL790, on Biochemical Measures of Synaptic Markers and Neurotransmission. J Pharmacol Exp Ther. 2020 Jul;374(1):126-133. doi: 10.1124/jpet.119.264754. Epub 2020 May 1.
citation: Waters S, Sonesson C, Svensson P, Tedroff J, Carta M, Ljung E, Gunnergren J, Edling M, Svanberg B, Fagerberg A, Kullingsjo J, Hjorth S, Waters N. Preclinical Pharmacology of [2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl](Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease. J Pharmacol Exp Ther. 2020 Jul;374(1):113-125. doi: 10.1124/jpet.119.264226. Epub 2020 May 1.
citation: Svenningsson P, Johansson A, Nyholm D, Tsitsi P, Hansson F, Sonesson C, Tedroff J. Safety and tolerability of IRL790 in Parkinson's disease with levodopa-induced dyskinesia-a phase 1b trial. NPJ Parkinsons Dis. 2018 Dec 6;4:35. doi: 10.1038/s41531-018-0071-3. eCollection 2018.