Overview

This is a Phase III, single-center, randomized, double-blind, placebo-controlled clinical trial designed to investigate the superiority of safinamide compared to a placebo in reducing Parkinson's Disease (PD)-related pain.

The trial plans to enroll 60 adult patients diagnosed with PD who experience motor fluctuations and chronic pain (lasting more than 3 months) despite receiving stable doses of levodopa.

Participants will be randomized in a 1:1 ratio to receive either oral safinamide or a matching placebo as an add-on therapy. The treatment regimen consists of 50 mg/day for the first week, increasing to 100 mg/day for the remaining 11 weeks, for a total treatment duration of 12 weeks.

The primary endpoint is to evaluate the mean change in pain severity from baseline to 12 weeks, measured using the 11-point Numeric Rating Scale (NRS) Secondary endpoints will assess additional qualitative and quantitative pain characteristics (KPPS, BPI, PD-PCS), motor symptoms and treatment complications (UPDRS Parts III and IV, Home Diary), quality of life (PDQ-39), and other non-motor symptoms (MDS-NMS).

The total expected duration of the clinical trial is 24 months.

Eligibility

Inclusion Criteria:

• Age ≥ 18 years; PD-related chronic pain (lasting more than 3 months) and motor fluctuations while receiving stable doses of L-dopa (alone or with other dopaminergic treatments) for at least 4 weeks prior to baseline (visit T0).
• Diagnosis of PD according to the International Parkinson and Movement Disorders Society (MDS) clinical diagnostic criteria.
• Disease duration since diagnosis of ≥ 3 years.
• Presence of motor fluctuations (\> 1.5 hours OFF time/day excluding morning akinesia)
• Hoehn and Yahr stage II-III during ON time.
• A history of pain symptoms for the last 12 weeks \[at least 4 points scored on the Numerical Rating Scale (NRS)\].
• Willing to participate in this study and able to understand and sign the written informed consent and the form privacy data.
• Be responsive to levodopa as per the MDS Clinical Diagnostic Criteria for Parkinson's disease, which define responsiveness as a clinically meaningful benefit to dopaminergic therapy, either documented objectively or subjectively.
• Be on stable daily doses of oral L-dopa (including controlled release \[CR\], immediate release \[IR\] or a combination of CR/IR), with and without benserazide/carbidopa, and optionally with a catechol-O-methyltransferase (COMT) inhibitor. Participants may also be receiving stable doses of dopamine agonists, anticholinergics and/or amantadine for at least 4 weeks prior to the screening visit.
• Participants must be able to speak and understand the Italian language.
• If female, participants must either be post-menopausal for at least one year, as self-reported by the patient, or, if of childbearing potential, must have a negative plasma human chorionic gonadotropin (HCG) test to exclude pregnancy at screening. Additionally, if of childbearing potential, patients will be required to undergo monthly urine pregnancy testing, scheduled at approximately day 30 and day 60, and the urine test at the final visit (T1). Moreover, women of childbearing potential must agree to use a highly effective method of contraception, starting 2 months before enrollment, throughout the entire duration of the study and for at least 30 days after the last dose of the study medication. Acceptable methods of contraception include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence \[Sexual abstinence is considered an acceptable method only if it reflects the participant's consistent and preferred lifestyle.\].

Exclusion Criteria:

• Concomitant therapy with monoamine oxidase B inhibitors.
• Patients experiencing severe, disabling peak-dose or biphasic dyskinesia, or unpredictable or widely swinging symptom fluctuations.
• De novo patients.
• Evidence of dementia suggested by a Mini-Mental Scale Examination (MMSE) score \< 24.
• Evidence of depression according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, DSM V.3.
• Treatment with antidepressant medications.
• Signs and symptoms suggestive of atypical parkinsonism.
• Severe and progressive medical illnesses other than PD.
• Concomitant diseases potentially causing acute or chronic pain (i.e., rheumatologic conditions, cancer, severe polyneuropathy, and spine injuries).
• Treatment with opioids, neuroleptics, barbiturates, phenothiazines, pregabalin, gabapentin.
• Any other contraindication according to the current Summary of product characteristics (SmPC) of safinamide.
• Previous neurosurgical intervention or stereotactic brain surgery for PD.
• Concomitant infusive device-aided therapies for PD.
• Drug and/or alcohol abuse within 12 months prior to the screening visit.
• Use of any investigational drug or device within 30 days prior to screening or 5 half-lives (whichever is the longest), or at any point during the study.
• Known allergy, sensitivity, or contraindications to the investigational medicinal products (IMPs), their excipients.
• Any clinically significant condition which, in the opinion of the Investigator, would be incompatible with study participation or pose a risk to the patient during the study.
• Moderate to severe liver failure as defined by the Child-Pugh classification score, or human immunodeficiency virus (HIV) infection.
• Treatment with monoamine oxidase inhibitors (MAOIs), pethidine, opiates, opioids, fluoxetine, fluvoxamine within 4 weeks prior to the screening visit. These drugs are not allowed throughout the study and up 2 weeks after the last dose of study drug.
• History of ophthalmologic conditions including any of the following: albinism, uveitis, retinitis pigmentosa, retinal degeneration, active retinopathy, severe progressive diabetic retinopathy, inherited retinopathy or family history of hereditary retinal disease.
• Pregnancy and breastfeeding.