A Double-blind, Randomised, Placebo-controlled, Rising Multiple Dose Study in Healthy Volunteers to Investigate the Effect of BIA 6-512 at Steady-state on the Levodopa Pharmacokinetics When Administered in Combination With a Single-dose of Levodopa/Benserazide 200/50 mg or With a Single-dose of Levodopa/Benserazide 200/50 mg Plus a Single-dose of Entacapone 200 mg
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 39
- 试验地点
- 1
- 主要终点
- Day 4 - Maximum observed plasma drug concentration (Cmax)
研究概览
简要总结
The purpose of the study was to To investigate whether the administration of BIA 6-512 (25 mg, 50 mg, 75 mg and 100 mg) at steady-state affects the pharmacokinetics of levodopa when administered in combination with a single-dose of immediate release levodopa/benserazide 200/50 mg or with a single-dose of immediate release levodopa/benserazide 200/50 mg plus a single-dose of entacapone 200 mg.
详细描述
Single centre, double-blind, randomised, placebo-controlled, rising multiple-dose study in four sequential groups of healthy male and female subjects. Eligible subjects were admitted to the Human Pharmacology Unit (UFHBIAL - Portela & Cª, SA) on the day prior to receiving the first study medication. Starting in the morning of Day 1 (first dose), subjects received BIA 6-512/Placebo thrice-daily until the morning of Day 5 (last dose). Concomitantly with the morning dose of BIA 6-512/Placebo, on Day 4 a levodopa/benserazide 200/50 mg (Madopar® 250) single-dose was administered. On Day 5, a Madopar® 250 single-dose and a entacapone 200 mg (Comtan®) single-dose were administered concomitantly with the morning dose of BIA 6-512/Placebo. In the morning of Day 4 and Day 5, products were administered in fasting of at least 8 hours and subjects remained fasted until 2 h post-dose. Subjects were resident in the UFH from admission (Day 0) until at least 24 h post last dose (Day 6); then, they were discharged and returned for the follow-up visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male or female subjects aged between 18 and 45 years, inclusive.
- •Subjects of body mass index (BMI) between 19 and 30 kg/m2, inclusive.
- •Subjects who were healthy as determined by pre-study medical history, physical examination, vital signs, complete neurological examination and 12-lead ECG.
- •Subjects who had negative tests for HBsAg, anti-HCVAb and HIV-1 and HIV-2 Ab at screening
- •Subjects who had clinical laboratory test results clinically acceptable at screening and admission.
- •Subjects who had a negative screen for alcohol and drugs of abuse at screening and admission.
- •Subjects who were non-smokers or who smoked ≤ 10 cigarettes or equivalent per day.
- •Subjects who were able and willing to gave written informed consent.
- •(If female) She was not of childbearing potential by reason of surgery or, if of childbearing potential, she used one of the following methods of contraception: double barrier, intrauterine device or abstinence.
- •(If female) She had a negative urine pregnancy test at screening and admission.
排除标准
- •Subjects who had a clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue diseases or disorders.
- •Subjects who had a clinically relevant surgical history.
- •Subjects who had a clinically relevant family history.
- •Subjects who had a history of relevant atopy.
- •Subjects who had a history of relevant drug hypersensitivity.
- •Subjects who had a history of alcoholism or drug abuse.
- •Subjects who consumed more than 14 units of alcohol a week.
- •Subjects who had a significant infection or known inflammatory process on screening or admission.
- •Subjects who had acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission.
- •Subjects who had used medicines within 2 weeks of admission that may affect the safety or other study assessments, in the investigator's opinion.
- •Subjects who had previously participated in a clinical trial with BIA 6-
- •Subjects who had used any investigational drug or participated in any clinical trial within 6 months prior to screening.
- •Subjects who had participated in more than 2 clinical trials within the 12 months prior to screening.
- •Subjects who had donated or received any blood or blood products within the 3 months prior to screening.
- •Subjects who were vegetarians, vegans or have medical dietary restrictions.
- •Subjects who cannot communicate reliably with the investigator.
- •Subjects who were unlikely to co-operate with the requirements of the study.
- •Subjects who were unwilling or unable to give written informed consent.
- •(If female) She was pregnant or breast-feeding.
- •(If female) She was of childbearing potential and she did not use an effective contraceptive method (double-barrier, intra-uterine device or abstinence) or she used oral contraceptives.
研究组 & 干预措施
Placebo
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the Placebo morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the Placebo morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Placebo (Drug)
Placebo
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the Placebo morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the Placebo morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Madopar® 250 (Drug)
Placebo
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the Placebo morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the Placebo morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Comtan® (Drug)
BIA 6-512 25 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 25 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 25 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: BIA 6-512 (Drug)
BIA 6-512 25 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 25 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 25 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Madopar® 250 (Drug)
BIA 6-512 25 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 25 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 25 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Comtan® (Drug)
BIA 6-512 50 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 50 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 50 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: BIA 6-512 (Drug)
BIA 6-512 50 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 50 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 50 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Madopar® 250 (Drug)
BIA 6-512 50 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 50 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 50 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Comtan® (Drug)
BIA 6-512 75 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 75 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 75 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: BIA 6-512 (Drug)
BIA 6-512 75 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 75 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 75 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Madopar® 250 (Drug)
BIA 6-512 75 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 75 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 75 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Comtan® (Drug)
BIA 6-512 100 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 100 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 100 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: BIA 6-512 (Drug)
BIA 6-512 100 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 100 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 100 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Madopar® 250 (Drug)
BIA 6-512 100 mg
Subjects were administered with those investigational products at approximately 8-h intervals, starting in the morning (approximately at 8h00) of Day 1 and finishing in the morning of Day 5 (last dose). On Day 4, concomitantly with the BIA 6-512 100 mg morning dose, one tablet of Madopar® 250 was administered. On Day 5, concomitantly with the BIA 6-512 100 mg morning dose, one tablet of Madopar® 250 and one tablet of Comtan® were administered.
干预措施: Comtan® (Drug)
结局指标
主要结局
Day 4 - Maximum observed plasma drug concentration (Cmax)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4
Day 4 - Time of occurrence of Cmax (tmax)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4
Day 4 - Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4
Day 4 - AUC from time zero to 8 h post-dose (AUC0-τ)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4
Day 4 - Apparent terminal elimination half-life, calculated from ln 2/λz (t1/2)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4
Day 4 - Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4
Day 5 - Maximum observed plasma drug concentration (Cmax)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
Day 5 - Time of occurrence of Cmax (tmax)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5
Day 5 - Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5
Day 5 - AUC from time zero to 8 h post-dose (AUC0-τ)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5
Day 5 - Apparent terminal elimination half-life, calculated from ln 2/λz (t1/2)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5
Day 5 - Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞)
时间窗: pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5
次要结局
未报告次要终点