Efficacy and Tolerability of Nebicapone in Parkinson's Disease Patients With "Wearingoff" Phenomenon

A Multicentre, Double-blind, Randomised, Active- and Placebo-controlled Trial to Investigate the Efficacy and Tolerability of Nebicapone in Parkinson's Disease Patients With "Wearingoff" Phenomenon Treated With Levodopa/Carbidopa or Levodopa/Benserazide

The purpose of this study was to investigate the effect on the "wearing-off" phenomenon of 3 different doses of nebicapone (NEB 50 mg, 100 mg and 150 mg), compared with entacapone and placebo when dministered concomitantly with existing treatment with levodopa plus a dopa decarboxylase inhibitor (DDCI: carbidopa or benserazide).

The study was conducted in 40 sites in Europe and South America: Argentina (6); Austria (2); Brazil (5); France (1); Hungary (4); Poland (7); Portugal (2); Romania (7); and Ukraine (6).

Multicentre study with a screening visit (Visit V1), a single-blind placebo run-in period of 1 or 2 weeks (Period 1, Visits V2 to V3), and an 8-week randomised, double-blind, activeand placebo-controlled, parallel-group (5 groups) treatment period (Period 2, Visits V3 to V7). In Hungary only: a 1-week tapering-off period was added by amendment #1HU. The dosage of nebicapone was to be tapered off stepwise during 6 days. This period was to end with a follow-up Visit V8.

Inclusion Criteria:

At Visit V1 (screening), patients had to be/have:

• Ability to comprehend and willingness to sign an informed consent form
• Aged 30 to 80 years, inclusive
• Diagnosis of idiopathic Parkinson's disease according to the Brain Bank Clinical Diagnosis Criteria of the UK Parkinson's Disease Society [Hughes et al, 1992]
• Disease severity less than Stage 5 (modified Hoehn & Yahr staging) while during the "off" time
• Treated with levodopa plus DDCI for at least 1 year with clear clinical improvement
• Treated with 4 to 8 (inclusive) daily doses of standard levodopa plus DDCI (bedtime dose of a slow-release formulation is permitted)
• Stable regimen of levodopa plus DDCI and other anti Parkinson drugs for at least 4 weeks before screening
• Signs of end-of-dose "wearing-off" phenomenon (end-of-dose deterioration) with average total daily "off" time while awake of at least 1.5 hours excluding the early morning pre first dose "off" period despite optimal anti Parkinson therapy, determined subjectively and objectively (observations of the investigator) for a minimum of 2 months before screening
• Ability to keep reliable diaries of motor fluctuations (alone or with family/caregiver assistance)
• Patient must be amenorrhoeic for at least 1 year or surgically sterile for at least 6 months before screening. In case of women of childbearing potential, patient must be using double-barrier contraceptive method.

At Visit V2 (entry to Period 1), patients had to have the results of laboratory tests acceptable by the investigator (not clinically relevant for the well being of the patient or for the purpose of the study).

At Visit V3 (randomisation), patients had to have:

• At least 80% treatment medication (levodopa/DDCI plus investigational product) compliance with the recommended dosage regimen during Period 1
• Self-rating diary charts filled in in accordance with the diary chart instructions; less than 3 errors per day are allowed
• Average of at least 1.5 "off" hours per day (excluding the early morning pre first dose "off" period) on the 3 day diaries, filled in on the 3 days preceding Visit V3, according to the self-rating diary charts completed during Period 1

Exclusion Criteria:

At Visit V1 (screening), patients were not to be/have:

• Non-idiopathic Parkinson's disease (atypical parkinsonism, symptomatic parkinsonism, Parkinson-plus syndrome)
• Dyskinesia disability score more than 3 in the Unified Parkinson's Disease Rating Scale (UPDRS) IV.A item 33
• Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criterion for dementia
• Major depressive episode within the 6 months before screening
• Treatment with entacapone, tolcapone, neuroleptics, antidepressants (except serotonin-specific reuptake inhibitors or imipraminics [desipramine, imipramine, clomipramine and amitriptyline]), monoamine oxidase inhibitors (except selegiline up to 10 mg/day in oral formulation or 1.25 mg/day in buccal absorption formulation or rasagiline up to 1 mg/day), or antiemetics (except domperidone) within the 3 months before screening
• Treatment with apomorphine within the previous month before screening
• Dosage change of concomitant anti Parkinson medication within 4 weeks of screening
• Any investigational product within the 3 months (or within 5 half-lives, whichever is longer) before screening
• A psychiatric or any medical condition that might place the patient at increased risk or interfere with assessment
• A clinically relevant electrocardiogram (ECG) abnormality
• A history or current evidence of heart disease, including but not limited to myocardial infarction, angina, congestive heart failure and cardiac arrhythmia
• Phaeochromocytoma
• Known hypersensitivity to the ingredients of products used
• Unstable concomitant disease being treated with changing doses of medication
• History or current evidence of any relevant disease in the context of this study, i.e. with respect to the safety of the patient or related to the study conditions, e.g. that may influence the absorption or metabolism (e.g. hepatic impairment) of the investigational drug
• Any abnormality in the liver enzymes above 2 times the upper limit of the normal range