Effect of Three Multiple-dose Regimens of BIA 9 1067 at Steady-state on the Levodopa Pharmacokinetics

Effect of Three Multiple-dose Regimens of BIA 9 1067 at Steady-state on the Levodopa Pharmacokinetics of a Single-dose of Immediate Release 100/25 mg Levodopa/Carbidopa and 100/25 mg Levodopa/Benserazide in Healthy Subjects

The purpose of this study is to determine the effect of BIA 9 1067 (5 mg, 15 mg and 50 mg) in steady-state conditions on the levodopa pharmacokinetics of a single dose of immediate-release levodopa/carbidopa 100/25 mg and of a single dose of immediate-release levodopa/benserazide 100/25 mg.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease (PD)
• Intervention / Treatment: Drug: Placebo; Drug: BIA 9-1067 5 mg; Drug: levodopa/carbidopa 100/25; Drug: levodopa/benserazide 100/25 mg; Drug: BIA 9-1067 25 mg

Detailed Description

A single-centre, randomized, double-blind, gender-balanced, placebo-controlled study in 4 groups of 18 healthy subjects each. This study consisted of a once-daily administration of BIA 9 1067 (5 mg, 15 mg or 50 mg) or placebo for 18 days. Twelve (12) hours after the BIA 9 1067 dose, a single-dose of levodopa/carbidopa 100/25 mg was administered on Day 11 and a single-dose of levodopa/benserazide 100/25 mg was administered on Day 18.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Rennes, France, F-35034
    • Biotrial

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:

• able to participate and willing to give written informed consent;
• male and female subjects;
• aged 18 to 45 years, inclusive;
• body mass index (BMI) between 18 and 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 electrocardiogram (ECG);
• negative tests for hepatitis B surface (HBs) antigen, anti-hepatitis C virus (HCV), human immunodeficiency virus-1 (HIV-1) and HIV-2 antibodies at screening;
• negative screen for drugs of abuse and alcohol at screening and admission to the treatment period;
• non-smokers or ex-smokers for at least 3 months;
• if sexually active, agreed to use a medically acceptable form of contraception throughout the study;
• if female of childbearing potential, had a negative human chorionic gonadotropin (HCG) beta serum pregnancy test at screening and admission to the treatment period.

Exclusion Criteria:

• who 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; or who had a history of relevant atopy;
• who had a significant infection or known inflammatory process at screening or admission to the treatment period; acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, heartburn) at the time of screening or admission to the treatment period;
• who were vegetarians, vegans or had medical dietary restrictions;
• who could not communicate reliably with the Investigator;
• who were unlikely to co-operate with the requirements of the study; history of hypersensitivity to BIA 9 1067, tolcapone, entacapone, levodopa, carbidopa, benserazide or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs;
• any significant cardiovascular (e.g. hypertension), hepatic, renal, respiratory (e.g. childhood asthma), gastrointestinal, endocrine (e.g. diabetes, dyslipidemia), immunologic, dermatological, haematological, neurologic, or psychiatric disease;
• 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.
• Consumption of 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);
• 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;
• donation of blood (i.e., 450 mL) within 60 days before study day 1;
• positive urine screening of ethyl alcohol or drugs of abuse upon admission to the treatment period;
• any history of tuberculosis and/or prophylaxis for tuberculosis; positive results to HIV, hepatitis B surface antigen (HBsAg) or anti-HCV tests;
• participation in any previous clinical study with BIA 9 1067;
• if female, being pregnant or breast-feeding.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BIA 9-1067 5 mg; 1 capsule of 5 mg + 2 capsules of placebo for 18 days levodopa/carbidopa 100/25 mg was administered on Day 11 levodopa/benserazide 100/25 mg was administered on Day 18.	Drug: Placebo; PLC, Placebo; Other Names: PLC, Placebo; Drug: BIA 9-1067 5 mg; OPC, Opicapone; Other Names: OPC, Opicapone; Drug: levodopa/carbidopa 100/25; immediate (standard) release levodopa/carbidopa 100/25; Other Names: Sinemet®; Drug: levodopa/benserazide 100/25 mg; immediate (standard) release levodopa/benserazide; Other Names: Madopar®
EXPERIMENTAL: BIA 9-1067 15 mg; 3 capsules of 5 mg for 18 days levodopa/carbidopa 100/25 mg was administered on Day 11 levodopa/benserazide 100/25 mg was administered on Day 18.	Drug: BIA 9-1067 5 mg; OPC, Opicapone; Other Names: OPC, Opicapone; Drug: levodopa/carbidopa 100/25; immediate (standard) release levodopa/carbidopa 100/25; Other Names: Sinemet®; Drug: levodopa/benserazide 100/25 mg; immediate (standard) release levodopa/benserazide; Other Names: Madopar®
EXPERIMENTAL: BIA 9-1067 50 mg; 2 capsules of BIA 9-1067 25 mg + 1 capsule of placebo for 18 days levodopa/carbidopa 100/25 mg was administered on Day 11 levodopa/benserazide 100/25 mg was administered on Day 18.	Drug: Placebo; PLC, Placebo; Other Names: PLC, Placebo; Drug: levodopa/carbidopa 100/25; immediate (standard) release levodopa/carbidopa 100/25; Other Names: Sinemet®; Drug: levodopa/benserazide 100/25 mg; immediate (standard) release levodopa/benserazide; Other Names: Madopar®; Drug: BIA 9-1067 25 mg; OPC, Opicapone; Other Names: OPC, Opicapone
PLACEBO_COMPARATOR: Placebo; 3 capsules of placebo for 18 days levodopa/carbidopa 100/25 mg was administered on Day 11 levodopa/benserazide 100/25 mg was administered on Day 18.	Drug: Placebo; PLC, Placebo; Other Names: PLC, Placebo; Drug: levodopa/carbidopa 100/25; immediate (standard) release levodopa/carbidopa 100/25; Other Names: Sinemet®; Drug: levodopa/benserazide 100/25 mg; immediate (standard) release levodopa/benserazide; Other Names: Madopar®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax - Maximum Plasma Concentration of Levodopa (Levodopa/Carbidopa)	Cmax - Maximum plasma concentration of levodopa following a single oral administration of 100/25 mg levodopa/carbidopa administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 11	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.
Tmax - Time to Reach Maximum Plasma Concentration of Levodopa (Levodopa/Carbidopa)	Tmax - Time to Reach maximum plasma concentration of levodopa following a single oral administration of 100/25 mg levodopa/carbidopa administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 11	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.
AUC0-∞ - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to Infinity (Levodopa/Carbidopa)	Levodopa pharmacokinetic parameters following a single oral administration of 100/25 mg levodopa/carbidopa administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 11	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.
AUC0-t - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to the Last Sampling Time at Which the Drug Concentration Was at or Above the Lower Limit of Quantification. (Levodopa/Carbidopa)	AUC0-t - Area under the plasma concentration-time curve (AUC) of levodopa from time zero to the last sampling time following a single oral administration of 100/25 mg levodopa/carbidopa administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 11	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.
Cmax - Maximum Plasma Concentration of Levodopa (Levodopa/Benserazide )	Levodopa pharmacokinetic parameters following a single oral administration of 100/25 mg levodopa/benserazide administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 18	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.
Tmax - Time to Reach Maximum Plasma Concentration of Levodopa (Levodopa/Benserazide)	Levodopa pharmacokinetic parameters following a single oral administration of 100/25 mg levodopa/benserazide administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 18	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.
AUC0-∞ - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to Infinity (Levodopa/Benserazide)	Levodopa pharmacokinetic parameters following a single oral administration of 100/25 mg levodopa/benserazide administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 18	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose.
AUC0-t - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to the Last Sampling Time at Which the Drug Concentration Was at or Above the Lower Limit of Quantification. (Levodopa/Benserazide)	Levodopa pharmacokinetic parameters following a single oral administration of 100/25 mg levodopa/benserazide administered 12 h after BIA 9-1067 (5 mg, 15 mg and 50 mg) or placebo on Day 18	pre-dose and at the following times post-dose: 0.5, 1, 1.5, 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: February 1, 2010
• Primary Completion (ACTUAL): July 1, 2010
• Study Completion (ACTUAL): July 1, 2010

Study Registration Dates

• First Submitted: January 24, 2012
• First Submitted That Met QC Criteria: June 19, 2014
• First Posted (ESTIMATE): June 23, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): December 24, 2015
• Last Update Submitted That Met QC Criteria: November 19, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Parkinson's disease (PD); Opicapone; BIA 9-1067
• 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; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors; Aromatic Amino Acid Decarboxylase Inhibitors; Levodopa; Carbidopa; Opicapone; Benserazide
• Other Study ID Numbers: BIA-91067-123