Efficacy and Safety of Safinamide (50 and 100mg/Day) Versus Placebo, in Patients With Mid-late Stage Parkinson's Disease

Inclusion Criteria:

• Patients are male or female, age 30-80 years, inclusive. If female, they must beeither post-menopausal for at least 12 months, surgically sterilized or have undergonehysterectomy. Patients older than 80 years, who meet all other entry criteria, will beconsidered for enrollment, with approval of the Newron Medical Expert.

• Patients must have a diagnosis of idiopathic Parkinson's disease of more than 5 yearsduration; the diagnosis should be based on medical history and neurologicalexamination. Patients with a duration of Parkinson's disease of at least 3 years, whomeet all other entry criteria, will be considered for enrollment, with approval of theCRO Medical Monitor.

• Patients must have a Hoehn and Yahr stage of I-IV during an "off" phase.

• Patients should be levodopa responsive and must have been receiving treatment with astable dose of levodopa [4-10 doses per day of any levodopa preparation (including CR,IR or a combination of CR/IR), plus benserazide/carbidopa; with or without addition ofa COMT inhibitor] and may be receiving concomitant treatment with stable doses of adopamine agonist and/or an anticholinergic at the screening visit. Patients willreceive the study medication as add-on therapy starting at baseline.

• Patients should have motor fluctuations, with >1.5 hours "off" time during the day.

• Patients must be able to maintain an accurate and complete diary (18-hour), with thehelp of a caregiver, recording "on" time, "on" time with minor dyskinesia, "on" timewith troublesome dyskinesia, "off" time, and time asleep.

• Patients must be able to understand and willing to sign an approved Informed Consentform.

Exclusion Criteria:

• The patient has any indication of forms of parkinsonism other than idiopathicParkinson's disease.

• If female, the patient is of childbearing potential, pregnant or lactating.

• The patient is in a late stage of Parkinson's disease, and is experiencing severe,disabling peak-dose or biphasic dyskinesia and/or unpredictable or widely swingingfluctuations in their symptoms.

• The patient has a current diagnosis of substance abuse (DSM-IV) or history of alcoholor drug abuse in the past 3 months.

• The patient has a current clinically significant gastrointestinal, renal, hepatic,endocrine, pulmonary or cardiovascular disease, including acute gastric ulcer,hypertension that is not well-controlled, asthma, chronic obstructive pulmonarydisease (COPD), and Type I diabetes. Patients with a history of gastric ulcer who havenot had an episode of acute gastritis in the last 6 months and are not currentlyexperiencing gastric pain will be eligible for inclusion.

• The patient has second- or third-degree atrio-ventricular block or sick sinussyndrome, uncontrolled atrial fibrillation, severe or unstable angina, congestiveheart failure, myocardial infarction within 3 months of the screening visit, or asignificant ECG abnormality, including QTc ≥ 450 msec (males) or ≥ 470 msec (females),where QTc is based on Bazett's correction method.

• The patient has participated in a previous clinical trial with safinamide.

• The patient has a concomitant disease likely to interfere with the study medication (e.g. capable of altering absorption, metabolism or elimination of the study drug).

• The patient has a history of psychosis (e.g. schizophrenia or psychotic depression),either previously or currently, or a score ≥ 3 on Item 2 (thought disorder) or 3 (depression) of the UPDRS Section I.

• The patient has evidence of dementia or cognitive dysfunction, as indicated by a MMSEscore < 22, or a score ≥ 3 on item 1 (mentation) of the UPDRS, Section I.

• The patient is depressed, as indicated by a GRID-HAMD (17-item scale) score > 17.

• The patient has a history of allergic response to anticonvulsants, levodopa, or otheranti-parkinsonian agents.

• The patient has a mental or physical condition (e.g., neurotic behaviour, cripplingdegenerative arthritis, or limb amputation), which would preclude performing efficacyor safety assessments.

• The patient has hypersenstivity or contraindications to MAO B inhibitors.

• The patient has a current history of severe dizziness or fainting on standing, due topostural hypotension.

• The patient has a neoplastic disorder, which is either currently active or has been inremission for less than one year.

• The patient has had stereotactic surgery as a treatment for his/her Parkinson'sdisease.

• The patient has participated in a previous clinical trial within 30 days of entry intothe study (screening visit) or has received treatment with any investigationalcompound within 30 days or 5 half-lives, whichever is longer, prior to screening. Theuse of an investigational drug other than safinamide during the study is notpermitted.

• The patient is receiving treatment of his/her depression with a MAO inhibitor (e.g.,selegiline), a tricyclic, or an SNRI (e.g., venlafaxine, duloxetine) at the screeningvisit. Note: Use of SSRIs will be permitted, provided the dose is kept as low aspossible and remains stable throughout the trial.

• The patient is receiving treatment of his/her parkinsonian symptoms with a MAOinhibitor. Note: Patients receiving amantadine, COMT inhibitors, DA agonists and/oranticholinergics will be eligible to enter the trial, provided they are on a stabledose at screening.

• The patient has received treatment with any agent known to significantly inhibit orinduce drug-metabolizing enyzmes (e.g., barbiturates, phenothiazines, etc.) within 4weeks preceding the screening visit.

• The patient has received treatment with opioids (e.g., tramadol, meperidinederivatives), in the 4 weeks prior to the screening visit.

• The patient has received treatment with a depot neuroleptic within one injectioncycle, or oral neuroleptics within 4 weeks prior to the screening visit. Patients whoare receiving a low dose of an oral neuroleptic for treatment of psychotic symptoms (e.g., hallucinations) related to their Parkinson's disease or anti-parkinsonianmedication, and who meet all other entry criteria, will be considered for enrollment,with approval of the CRO Medical Monitor. The Investigator must agree not to increasethe dose of the oral neuroleptic during the trial, unless required for significantworsening.

• The patient has received treatment with a drug that has hepatotoxic potential, e.g.,tamoxifen, within 4 weeks, or received radiation therapy or a drug with cytotoxicpotential, e.g, chemotherapy, within one year prior to the screening visit.

• The patient has a history or a current diagnosis of HIV, tests positive for HepatitisB surface antigen, tests positive for Hepatitis B core antibody, but negative forHepatitis B surface antibody, or tests positive for Hepatitis C antibodies.

• The patient has any abnormality that the investigator deems to be clinically relevant,either on medical history, physical examination, ECG or a diagnostic laboratory test.

• In the judgment of the Clinical Investigator the patient is likely to be non-compliantor uncooperative during the study.

• Ophthalmologic history including any of the following conditions: albino patients,family history of hereditary retinal disease, progressive and/or severe diminution ofvisual acuity (i.e., 20/70), retinitis pigmentosa, retinal pigmentation due to anycause, any active retinopathy or ocular inflammation (uveitis), or progressive, severediabetic retinopathy.