Effect of BIA 6-512 at Steady-state on the Levodopa Pharmacokinetics

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

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.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Placebo; Drug: Madopar® 250; Drug: Comtan®; Drug: BIA 6-512

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• Portugal
  • S. Mamede do Coronado, Portugal, 4745-457
    • Human Pharmacology Unit (UFH) - BIAL - Portela & Cª, SA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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 6-512.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: DOUBLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Placebo; 1 capsule of placebo [to be taken orally, with 240 mL of potable water]; Drug: Madopar® 250; Levodopa/benserazide immediate release tablets 200mg/50mg [to be taken orally, with 240 mL of potable water]; Drug: Comtan®; Entacapone 200 mg tablets [to be taken orally, with 240 mL of potable water]
EXPERIMENTAL: 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.	Drug: Madopar® 250; Levodopa/benserazide immediate release tablets 200mg/50mg [to be taken orally, with 240 mL of potable water]; Drug: Comtan®; Entacapone 200 mg tablets [to be taken orally, with 240 mL of potable water]; Drug: BIA 6-512; 1 capsule of BIA 6-512 25mg or 1 capsule of BIA 6-512 50 mg or 1 capsule of BIA 6-512 75 mg or 1 capsule of BIA 6-512 100 mg [to be taken orally, with 240 mL of potable water]; Other Names: Trans-resveratrol
EXPERIMENTAL: 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.	Drug: Madopar® 250; Levodopa/benserazide immediate release tablets 200mg/50mg [to be taken orally, with 240 mL of potable water]; Drug: Comtan®; Entacapone 200 mg tablets [to be taken orally, with 240 mL of potable water]; Drug: BIA 6-512; 1 capsule of BIA 6-512 25mg or 1 capsule of BIA 6-512 50 mg or 1 capsule of BIA 6-512 75 mg or 1 capsule of BIA 6-512 100 mg [to be taken orally, with 240 mL of potable water]; Other Names: Trans-resveratrol
EXPERIMENTAL: 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.	Drug: Madopar® 250; Levodopa/benserazide immediate release tablets 200mg/50mg [to be taken orally, with 240 mL of potable water]; Drug: Comtan®; Entacapone 200 mg tablets [to be taken orally, with 240 mL of potable water]; Drug: BIA 6-512; 1 capsule of BIA 6-512 25mg or 1 capsule of BIA 6-512 50 mg or 1 capsule of BIA 6-512 75 mg or 1 capsule of BIA 6-512 100 mg [to be taken orally, with 240 mL of potable water]; Other Names: Trans-resveratrol
EXPERIMENTAL: 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.	Drug: Madopar® 250; Levodopa/benserazide immediate release tablets 200mg/50mg [to be taken orally, with 240 mL of potable water]; Drug: Comtan®; Entacapone 200 mg tablets [to be taken orally, with 240 mL of potable water]; Drug: BIA 6-512; 1 capsule of BIA 6-512 25mg or 1 capsule of BIA 6-512 50 mg or 1 capsule of BIA 6-512 75 mg or 1 capsule of BIA 6-512 100 mg [to be taken orally, with 240 mL of potable water]; Other Names: Trans-resveratrol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day 4 - Maximum observed plasma drug concentration (Cmax)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
Day 4 - Time of occurrence of Cmax (tmax)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
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)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
Day 4 - AUC from time zero to 8 h post-dose (AUC0-τ)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
Day 4 - Apparent terminal elimination half-life, calculated from ln 2/λz (t1/2)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
Day 4 - Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 4	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8 and 16 hours post-dose
Day 5 - Maximum observed plasma drug concentration (Cmax)		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)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
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)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
Day 5 - AUC from time zero to 8 h post-dose (AUC0-τ)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
Day 5 - Apparent terminal elimination half-life, calculated from ln 2/λz (t1/2)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose
Day 5 - Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞)	BIA 6-512, levodopa, 3-OMD and entacapone pharmacokinetic parameters on day 5	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 16 and 24 hours post-dose

Collaborators and Investigators

• Sponsor: Bial - Portela C S.A.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 26, 2006
• Primary Completion (ACTUAL): July 11, 2006
• Study Completion (ACTUAL): July 11, 2006

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: March 28, 2017
• First Posted (ACTUAL): March 29, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 30, 2017
• Last Update Submitted That Met QC Criteria: March 29, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Dopamine Agents; Antioxidants; Resveratrol; Benserazide, levodopa drug combination
• Other Study ID Numbers: BIA-6512-106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No