Pharmacokinetics of Rising Single-doses of BIA 6-512 and Their Effect on the Levodopa Pharmacokinetics

A Double-blind, Randomised, Placebo-controlled Study in Healthy Volunteers to Investigate the Tolerability and Pharmacokinetics of Rising Single-doses of BIA 6-512 and Their Effect on the Levodopa Pharmacokinetics When Administered in Combination With a Single-dose of Levodopa/Carbidopa 100/25 mg or With a Single-dose of Levodopa/Carbidopa 100/25 mg Plus a Single-dose of Entacapone 200 mg

To investigate the effect of rising oral single-doses of BIA 6-512 (25 mg, 50 mg, 100 mg and 200 mg) on levodopa pharmacokinetics when administered in combination with a single-dose of immediate release levodopa/carbidopa 100/25 mg (Sinemet® 100/25) or with a single-dose of Sinemet® 100/25 plus a single-dose of entacapone (Comtan®) 200 mg and to assess the tolerability and safety of rising single oral doses of BIA 6-512 when administered in combination with a single-dose of Sinemet® 100/25 or with a single-dose of Sinemet® 100/25 plus a single-dose of Comtan® 200 mg.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Placebo oral capsule; Drug: Sinemet® 100/25; Drug: Comtan®; Drug: BIA 6-512 25 mg; Drug: BIA 6-512 100 mg

Detailed Description

Single centre, double-blind, randomised, placebo-controlled study in four sequential groups of healthy subjects. Eligible subjects were admitted to the UFH on the day prior to receiving the first study medication. On the morning of the first dosing day (Day 1), subjects received BIA 6-512/Placebo concomitantly with Sinemet® 100/25; on the morning of the second dosing day (Day 2), subjects received BIA 6-512/Placebo concomitantly with Sinemet® 100/25 and Comtan® 200 mg. Products were administered in fasting conditions (at least 8 hours). Subjects remained confined in the UFH from admission (Day 0) until at least 24 h post last dose (Day 3); then, they were discharged and will return for the follow-up visit.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 1

Contacts and Locations

Study Locations

• Portugal
  • S. Mamede do Coronado, Portugal, 4745-457
    • Human Pharmacology Unit (UFH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• 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 clinical laboratory tests clinically acceptable at screening and admission.
• Subjects who had negative tests for HBsAg, anti-HCVAb and anti-HIV-1 and anti-HIV-2 Ab at screening.
• Subjects who had a negative screen for alcohol and drugs of abuse at screening and admission.
• Subjects who were non-smokers or who smoked less than 10 cigarettes or equivalent per day.
• Subjects who were able and willing to give written informed consent.
• (If female) She was sterile 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 did not conform to the above inclusion criteria, OR
• 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 21 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 at the time of screening or admission (e.g., nausea, vomiting, diarrhoea, heartburn).
• Subjects who had used prescription or over-the-counter medication within 2 weeks of admission.
• Subjects who had used any investigational drug or participated in any clinical trial within 3 months prior to screening.
• Subjects who had donated or received any blood or blood products within 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.
• (If female) She was pregnant or breast-feeding.
• (If female) She was of childbearing potential and she did not use an approved effective contraceptive method or she used oral contraceptives.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1 (BIA 6-512 25 mg + Placebo); Single-doses were prepared as follows: BIA 6-512 25 mg dose = 1 capsule of 25 mg plus 1 capsule of placebo In all groups, placebo recipients received 2 capsules of placebo. BIA 6-512/Placebo capsules and Sinemet® 100/25 and Comtan® tablets were administered simultaneously, by oral route, in fasting conditions.	Drug: Placebo oral capsule; Matching placebo capsules. Oral administration.; Drug: Sinemet® 100/25; Single-dose of immediate release levodopa/carbidopa 100/25 mg consisted of 1 tablet of Sinemet® 100/25. Route of administration: Oral.; Drug: Comtan®; Single-dose of entacapone 200 mg consisted of 1 tablet of Comtan®. Route of administration: Oral.; Drug: BIA 6-512 25 mg; BIA 6-512 capsules strengths 25 mg. Oral administration.
Experimental: Group 2 (BIA 6-512 50 mg + Placebo); Single-doses were prepared as follows: BIA 6-512 50 mg dose = 2 capsules of 25 mg In all groups, placebo recipients received 2 capsules of placebo. BIA 6-512/Placebo capsules and Sinemet® 100/25 and Comtan® tablets were administered simultaneously, by oral route, in fasting conditions.	Drug: Placebo oral capsule; Matching placebo capsules. Oral administration.; Drug: Sinemet® 100/25; Single-dose of immediate release levodopa/carbidopa 100/25 mg consisted of 1 tablet of Sinemet® 100/25. Route of administration: Oral.; Drug: Comtan®; Single-dose of entacapone 200 mg consisted of 1 tablet of Comtan®. Route of administration: Oral.; Drug: BIA 6-512 25 mg; BIA 6-512 capsules strengths 25 mg. Oral administration.
Experimental: Group 3 (BIA 6-512 100 mg + Placebo); Single-doses were prepared as follows: BIA 6-512 100 mg dose = 1 capsule of 100 mg plus 1 capsule of placebo In all groups, placebo recipients received 2 capsules of placebo. BIA 6-512/Placebo capsules and Sinemet® 100/25 and Comtan® tablets were administered simultaneously, by oral route, in fasting conditions.	Drug: Placebo oral capsule; Matching placebo capsules. Oral administration.; Drug: Sinemet® 100/25; Single-dose of immediate release levodopa/carbidopa 100/25 mg consisted of 1 tablet of Sinemet® 100/25. Route of administration: Oral.; Drug: Comtan®; Single-dose of entacapone 200 mg consisted of 1 tablet of Comtan®. Route of administration: Oral.; Drug: BIA 6-512 100 mg; BIA 6-512 capsules strengths 100 mg. Oral administration.
Experimental: Group 4 (BIA 6-512 200 mg + Placebo); Single-doses were prepared as follows: BIA 6-512 200 mg dose = 2 capsules of 100 mg In all groups, placebo recipients received 2 capsules of placebo. BIA 6-512/Placebo capsules and Sinemet® 100/25 and Comtan® tablets were administered simultaneously, by oral route, in fasting conditions.	Drug: Placebo oral capsule; Matching placebo capsules. Oral administration.; Drug: Sinemet® 100/25; Single-dose of immediate release levodopa/carbidopa 100/25 mg consisted of 1 tablet of Sinemet® 100/25. Route of administration: Oral.; Drug: Comtan®; Single-dose of entacapone 200 mg consisted of 1 tablet of Comtan®. Route of administration: Oral.; Drug: BIA 6-512 100 mg; BIA 6-512 capsules strengths 100 mg. Oral administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed plasma drug concentration (Cmax) - Day 1	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) on Day 1 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25)	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Time at which the Cmax occurred (tmax) - Day 1	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) on Day 1 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25)	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Area under the plasma concentration versus time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t) - Day 1	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) on Day 1 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25)	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
AUC from time zero to the infinity (AUC0-∞) - Day 1	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) on Day 1 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25)	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Elimination rate constant (λz) - Day 1	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) on Day 1 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25)	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Apparent elimination half-life (t1/2) - Day 1	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) on Day 1 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25)	pre-dose, ¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Maximum observed plasma drug concentration (Cmax) - Day 2	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) and entacapone on day 2 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25) plus 1 tablet of entacapone 200 mg (Comtan®). Administration occurred 24 h after the time of administration in Day 1.	¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Time at which the Cmax occurred (tmax) - Day 2	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) and entacapone on day 2 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25) plus 1 tablet of entacapone 200 mg (Comtan®). Administration occurred 24 h after the time of administration in Day 1.	¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Area under the plasma concentration versus time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t) - Day 2	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) and entacapone on day 2 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25) plus 1 tablet of entacapone 200 mg (Comtan®). Administration occurred 24 h after the time of administration in Day 1.	¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
AUC from time zero to the infinity (AUC0-∞) - Day 2	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) and entacapone on day 2 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25) plus 1 tablet of entacapone 200 mg (Comtan®). Administration occurred 24 h after the time of administration in Day 1.	¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Elimination rate constant (λz) - Day 2	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) and entacapone on day 2 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25) plus 1 tablet of entacapone 200 mg (Comtan®). Administration occurred 24 h after the time of administration in Day 1.	¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Apparent elimination half-life (t1/2) - Day 2	Pharmacokinetic parameters for BIA 6-512, levodopa, 3-O-methyldopa (3-OMD) and entacapone on day 2 - Day of administration of BIA 6-512/Placebo concomitantly with 1 tablet of levodopa/carbidopa 100/25 mg (Sinemet® 100/25) plus 1 tablet of entacapone 200 mg (Comtan®). Administration occurred 24 h after the time of administration in Day 1.	¼, ½, ¾, 1, 1½, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

Collaborators and Investigators

• Sponsor: Bial - Portela C S.A.

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2004
• Primary Completion (Actual): February 28, 2005
• Study Completion (Actual): February 28, 2005

Study Registration Dates

• First Submitted: March 21, 2017
• First Submitted That Met QC Criteria: March 21, 2017
• First Posted (Actual): March 27, 2017

Study Record Updates

• Last Update Posted (Actual): March 27, 2017
• Last Update Submitted That Met QC Criteria: March 21, 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; Immunologic Factors; Dopamine Agonists; Dopamine Agents; Adjuvants, Immunologic; Antiparkinson Agents; Anti-Dyskinesia Agents; Carbidopa, levodopa drug combination
• Other Study ID Numbers: BIA-6512-102

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 device product: No