The Effect of BIA 9-1067 at Steady-state on the Levodopa Pharmacokinetics

This study was a single-centre, randomized, double-blind, gender-balanced, placebo-controlled study in 4 groups of 20 healthy subjects each (10 male and 10 female). The clinical part included a screening examination within 3 weeks before the first institutionalization, an ambulatory period of 11 days (from Day 1 evening to Day 11 evening), during which the subjects returned to the clinical unit every evening, followed by an institutionalization of 1.5 days (from Day 11 evening to Day 13 morning (i.e. 14 h after the third administration of levodopa/carbidopa). Then, a follow-up visit at 5 to 9 days after collection of the last PK blood sample (i.e. Day 13). The maximum total duration of the clinical study, including the 21-day screening period and the post-study follow-up, was expected to be about 39 to 43 days.

Inclusion criteria

• Healthy male and female volunteers 18 to 45 years old (inclusive),
• Body Mass Index (BMI) in normal range (18-30 kg/m²),
• Healthy as determined by the Investigator on the basis of medical history, physical examination, clinical laboratory test results, vital signs, complete neurological examination and 12-lead ECG (electrocardiogram),
• Negative tests for Hepatitis B surface antigen (HBsAG), anti-Hepatitis C virus (HCV) antibodies and Human immunodeficiency virus (HIV) -1 and HIV-2 antibodies at screening,
• Negative screen for drugs of abuse and alcohol at screening and admission to the treatment period,
• If of childbearing potential (i.e. except if they had been sterilized for at least 3 months or postmenopausal for at least one year - the menopause was defined by a follicule stimulating hormone (FSH) level > 30 IU/L): used a non hormonal acceptable contraception method, i.e. intra-uterine device, condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository for all the duration of the study,
• If female of childbearing potential, had a negative human chorionic gonadotropin (HCG) beta serum pregnancy test at screening and urinary pregnancy test at admission to both ambulatory and confinement periods,
• Non-smokers or ex-smokers for at least 3 months,
• Able to communicate well with the Investigator and research staff and to comply with the requirements of the entire study,
• Provision of written informed consent to participate as shown by a signature on the volunteer consent form,
• Registered with the French Social Security in agreement with the French law on biomedical experimentation

Exclusion criteria

• Did not conform to the above inclusion criteria, or in case of volunteers who had a clinically relevant surgical history, a clinically relevant family history; had a history of relevant atopy,
• Had a significant infection or known inflammatory process at screening or admission to the treatment period; acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission to the treatment period,
• Were vegetarians, vegans or had medical dietary restrictions,
• Could not communicate reliably with the Investigator,
• Were unlikely to co-operate with the requirements of the study; history of hypersensitivity to OPC, tolcapone, ENT, levodopa, carbidopa, benserazide or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs,
• Had any significant cardiovascular (e.g. hypertension), hepatic, renal, respiratory (e.g. childhood asthma), gastrointestinal, endocrine (e.g. diabetes, dyslipidemia), immunologic, dermatological, hematological, neurological, or psychiatric disease,
• Presented any clinically significant illness in the previous 28 days before Day 1 of this study; history of drug abuse within 1 year before study Day 1; history of alcoholism within 1 year before Day 1,
• Had taken any prescribed or over the counter drug (including antacid drug), with the exception of paracetamol (up to 3 g per day) within 2 weeks prior to the dose administration,
• Consumed more than 50 g of ethanol per day (12.5 cL glass of 10° [10%] wine = 12 g; 4 cL of aperitif, 42° [42%] whiskey = 17 g; 25 cL glass of 3° [3%] beer = 7.5 g; 25 cL glass of 6° [6%] beer = 15 g,
• Drank more than 8 cups daily of beverage containing caffeine,
• Had poor motivation, intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with the protocol requirements or inability to cooperate adequately, inability to understand and to observe the instructions of the physician,
• Had received any experimental drug within the exclusion period defined in the National Register for Healthy Volunteers of the French Ministry of Health,
• Forfeited their freedom by administrative or legal award or were under guardianship,
• Had undergone surgery or had donated blood (i.e. 450 mL) within 12 weeks before study Day 1,
• Had positive urine screening of ethyl alcohol or drugs of abuse upon admission to the treatment period,
• Had any history of tuberculosis and/or prophylaxis for tuberculosis; positive results to HIV, HBsAg or anti-HCV tests; participation in any previous clinical study with OPC,
• If female, was pregnant or breast-feeding.