A Clinical Study of Mesdopetam in Patients With Parkinson's Disease Experiencing Levodopa Induced Dyskinesia

Parkinson Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04435431
• Other study ID #: IRL790C005
• Status: Completed
• Phase: Phase 2
• Start date: October 29, 2020
• Est. completion date: December 9, 2022

Study information

• Verified date: February 2024
• Source: Integrative Research Laboratories AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 155
• Est. completion date: December 9, 2022
• Est. primary completion date: December 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 79 Years

Eligibility

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.

Related Conditions & MeSH terms

• Dyskinesias
• Parkinson Disease

Intervention

Drug:
• Mesdopetam
Oral use
• Placebo
Oral use

Locations

Country	Name	City	State
France	Centre Hospitalier Regional Universitaire de Lille	Lille
France	CHU Dupuytren 1 - Neurologie	Limoges
France	CHU Carémeau	Nimes
France	CHU de Poitiers	Poitiers
France	CHU Rennes-Pontchaillou	Rennes
France	CHU Charles Nicolle; Service de Neurologie	Rouen
Israel	Rambam Health Care Campus, Department of Neurology	Haifa
Israel	Hadassah University Hospital-Ein Kerem, Department of Neurology	Jerusalem
Israel	Rabin Medical Centre - Beilinson Hospital, Department of Neurology	Petah Tikva
Israel	The Chaim Sheba Medical Centre, Department of Neurology	Ramat Gan
Israel	Tel Aviv Sourasky Medical Centre; Movement Disorders Unit	Tel Aviv
Italy	IRCCS - Ospedale "San Martino"	Genova
Italy	Azienda Ospedaliera di Padova	Padova
Italy	Fondazione Policlinico Gemelli IRCCS	Roma
Italy	IRCCS San Raffaele Pisana	Roma
Italy	AOU San Giovanni di Dio e Ruggi d'Aragona, Clinica Neurologica	Salerno
Poland	Centrum Medyczne Neuromed	Bydgoszcz
Poland	Specjalistyczna Praktyka Lekarska	Katowice
Poland	Centrum Medyczne PLEJADY	Kraków
Poland	Krakowska Akademia Neurologii	Kraków
Poland	Specjalistyczne Gabinety Sp z o.o.	Kraków
Poland	Instytut Zdrowia	Oswiecim
Poland	Neuro-Care	Siemianowice Slaskie
Poland	Next Stage sp.z o.o.	Warsaw
Poland	Centrum Medyczne NeuroProtect	Warszawa
Poland	ClinHouse Centrum Medyczne	Zabrze
Serbia	Clinical Hospital Center Zvezdara, Clinical department of Neurology	Belgrade
Serbia	University Clinical Center of Serbia, Clinic for Neurology	Belgrade
Serbia	University Clinical Center Kragujevac, Clinic for Neurology (Site 601)	Kragujevac
Serbia	University Clinical Center Kragujevac, Clinic for Neurology (Site 602)	Kragujevac
United States	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida
United States	Colorado Springs Neurological Associates	Colorado Springs	Colorado
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	NeuroStudies.net, LLC	Decatur	Georgia
United States	University of Kentucky, Department of Neurology	Lexington	Kentucky
United States	Collaborative Neuroscience Research (CNS Research)	Long Beach	California
United States	Avantis Clinical Research	Miami	Florida
United States	Elias Research Associates (Allied Biomedical Research Institute)	Miami	Florida
United States	Pharmax Research of South Florida, Inc.	Miami	Florida
United States	Life Medical Research Group Corp	Miami Gardens	Florida
United States	Parkinson's Disease and Movement Disorders Center of Silicon Valley	Palo Alto	California
United States	Movement Disorders Center of Arizona	Scottsdale	Arizona
United States	Inland Northwest Research	Spokane	Washington
United States	The Movement Disorder Clinic of Oklahoma	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
Integrative Research Laboratories AB

Countries where clinical trial is conducted

United States,  France,  Israel,  Italy,  Poland,  Serbia, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	This is a self-administered diary where patients assess their motor state every half hour during 24 hours. ON time without troublesome dyskinesia measures time when the medication is working without causing troublesome dyskinesia.	Baseline to end of treatment (week 12)
Secondary	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.	The scoring range is 0-88, where higher score means more dyskinesia.	Baseline to end of treatment (week 12)
Secondary	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.	The scoring range is 0-60, where higher score means more disability associated with dyskinesia.	Baseline to end of treatment (week 12)
Secondary	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)	This scale is a patient reported outcome measure assessing motor aspects of experiences of daily living. Minimum score is 0 and maximum score is 52. A higher score means more Parkinson's disease motor symptoms.	Baseline to end of treatment (week 12)
Secondary	Change From Baseline in Average Daily Hours of OFF-time (With Mesdopetam Compared to Placebo).	This is a self-administered diary where patients assess their motor state every half hour during 24 hours. OFF time means time means daily time spent when the medication is not working.	Baseline to end of treatment (week 12)