Pharmacokinetic-pharmacodynamic Interaction Between Each of Three Different Single Doses of BIA 9-1067 and a Single-dose of Controlled-release 100/25 mg Levodopa/Carbidopa

Study Overview
=================
Brief Summary
-----------------
To investigate the effect of three single oral doses of BIA 9-1067 (25 mg, 50 mg and 100 mg) on the levodopa pharmacokinetics when administered in combination with a single-dose of controlled-release levodopa/carbidopa 100/25 mg (Sinemet® CR 100/25)

Detailed Description
-----------------
Single centre, double-blind, randomized, placebo-controlled, crossover study with four consecutive single-dose treatment periods. The washout period between doses was to be at least 14 days. On each treatment period, after completion of pre-dose assessments, BIA 9-1067/Placebo was to be administered concomitantly with the dose of Sinemet® CR 100/25; post-dose assessments were to be completed and subjects were to be discharged 72 h post-dose. Subjects were to attend four treatment periods and were to receive a different dose of BIA 9-1067 (25 mg, 50 mg and 100 mg) or placebo during each of these treatment periods.

Official Title
-----------------
Pharmacokinetic-pharmacodynamic Interaction Between Each of Three Different Single Doses of BIA 9-1067 and a Single-dose of Controlled-release 100/25 mg Levodopa/Carbidopa: a Double-blind, Randomized, Four-way Crossover, Placebo-controlled Study in Healthy Male Subjects

Conditions
-----------------
Parkinson's Disease (PD)

Intervention / Treatment
-----------------
* Drug: BIA 9-1067
* Drug: Placebo
* Drug: Sinemet® CR 100/25


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Availability for the entire study period and willingness to adhere to the protocol requirements as evidenced by the informed consent form (ICF) duly read, signed and dated by the volunteer prior to participation in the study. Male volunteers. Volunteers of at least 18 years of age but not older than 45 years. Volunteers with body mass index (BMI) greater than or equal to 19 and below 30 kg/m2. Volunteers who were non- or ex-smokers. An ex-smoker is defined as someone who completely stopped smoking for at least 12 months before day 1 of this study. Volunteers who were healthy as determined by pre-study (at screening) medical history, physical examination, vital signs, complete neurological examination and 12-lead ECG. Volunteers who had clinical laboratory test results judged clinically acceptable (within the laboratory's stated normal range; if not within this range, they must had been without any clinical significance) at screening and admission to first treatment period. Volunteers who had negative tests for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibodies (HCV Ab), and Human immunodeficiency viruses -1 and -2 antibodies (HIV-1 and HIV-2 Ab) at screening. Volunteers who had negative screen of ethyl alcohol and drugs of abuse at screening. Due to unknown risks and potential harm to the unborn fetus, sexually active men must have agreed to use a medically acceptable form of contraception throughout the study. Exclusion Criteria: Volunteers who did not conform to the above inclusion criteria, or in case of Volunteers who had a clinically relevant surgical history. Volunteers who had a clinically relevant family history. Volunteers who had a history of relevant atopy. Volunteers who had a significant infection or known inflammatory process at screening or first admission. Volunteers who had acute gastrointestinal symptoms at the time of screening or first admission (e.g., nausea, vomiting, diarrhoea, heartburn). Volunteers who were vegetarians, vegans or have medical dietary restrictions. Volunteers who could not communicate reliably with the investigator. Volunteers who were unlikely to co-operate with the requirements of the study. Significant history of hypersensitivity to BIA 9-1067, tolcapone, entacapone, levodopa, carbidopa or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs. Presence of significant gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs or known to potentiate or predispose to undesired effects. History of significant gastrointestinal, liver or kidney disease that may affect drug bioavailability. Presence or history of significant cardiovascular, pulmonary, hematologic, neurologic, psychiatric, lymphatic, musculoskeletal, genitourinary, endocrine, immunologic, dermatologic or connective tissue disease. Suicidal tendency, history of or disposition to seizures, state of confusion, clinically relevant psychiatric diseases. Presence of significant heart disease or disorder according to ECG. Presence of suspicious undiagnosed skin lesions or a history of melanoma. Previous history of Neuroleptic Malignant Syndrome (NMS) and/or nontraumatic rhabdomyolysis. Presence or history of significant glaucoma. Used of prescription medications including monoamine oxidase (MAO) inhibitors within 28 days before day 1 of the study. Used of over-the-counter (OTC) products within 7 days before day 1 of the study. Maintenance therapy with any drug, or significant history of drug dependency (drug abuse) or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic). Any clinically significant illness in the previous 28 days before day 1 of this study. Used of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin and rifampicin), in the previous 28 days before day 1 of this study. Volunteers who took an Investigational Product (in another clinical trial) or donated 50 mL or more of blood in the previous 28 days before day 1 of this study. 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 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the previous 56 days before day 1 of this study. Positive urine screening of ethyl alcohol or drugs of abuse at admission to any treatment period. 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 BIA 9-1067 within 84 days before day 1 of the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Period 1: BIA 9-1067 25 mg Period 2: BIA 9-1067 50 mg Period 3: BIA 9-1067 100 mg Period 4: Placebo BIA 9-1067/Placebo was to be administered concomitantly with the dose of Sinemet® CR 100/25 (Single-dose of controlled-release levodopa/carbidopa 100/25 mg: 1 tablet of Sinemet® CR 100/25.) | Drug: BIA 9-1067<br>* OPC, Opicapone<br>* Other names: OPC, Opicapone;Drug: Placebo<br>* PLC, Placebo<br>* Other names: PLC, Placebo;Drug: Sinemet® CR 100/25<br>* Controlled-release levodopa/carbidopa 100/25 mg<br>|
| Experimental: Group 2<br>Period 1: BIA 9-1067 50 mg Period 2: BIA 9-1067 100 mg Period 3: Placebo Period 4: BIA 9-1067 25 mg BIA 9-1067/Placebo was to be administered concomitantly with the dose of Sinemet® CR 100/25 (Single-dose of controlled-release levodopa/carbidopa 100/25 mg: 1 tablet of Sinemet® CR 100/25.) | Drug: BIA 9-1067<br>* OPC, Opicapone<br>* Other names: OPC, Opicapone;Drug: Placebo<br>* PLC, Placebo<br>* Other names: PLC, Placebo;Drug: Sinemet® CR 100/25<br>* Controlled-release levodopa/carbidopa 100/25 mg<br>|
| Experimental: Group 3<br>Period 1: BIA 9-1067 100 mg Period 2: Placebo Period 3: BIA 9-1067 25 mg Period 4: BIA 9-1067 50 mg BIA 9-1067/Placebo was to be administered concomitantly with the dose of Sinemet® CR 100/25 (Single-dose of controlled-release levodopa/carbidopa 100/25 mg: 1 tablet of Sinemet® CR 100/25.) | Drug: BIA 9-1067<br>* OPC, Opicapone<br>* Other names: OPC, Opicapone;Drug: Placebo<br>* PLC, Placebo<br>* Other names: PLC, Placebo;Drug: Sinemet® CR 100/25<br>* Controlled-release levodopa/carbidopa 100/25 mg<br>|
| Experimental: Group 4<br>Period 1: Placebo Period 2: BIA 9-1067 25 mg Period 3: BIA 9-1067 50 mg Period 4: BIA 9-1067 100 mg Subjects were to attend four treatment periods and were to receive a different dose of BIA 9-1067 (25 mg, 50 mg and 100 mg) or placebo during each of these treatment periods. | Drug: BIA 9-1067<br>* OPC, Opicapone<br>* Other names: OPC, Opicapone;Drug: Placebo<br>* PLC, Placebo<br>* Other names: PLC, Placebo;Drug: Sinemet® CR 100/25<br>* Controlled-release levodopa/carbidopa 100/25 mg<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax - Maximum Observed Plasma Concentration | Cmax - Maximum observed plasma concentration of levodopa | pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 h post-dose | 
| AUC0-t - Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t - Area under the plasma concentration-time curve to last measurable time point for levodopa | pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 h post-dose | 
| AUC0-∞ - Area Under the Plasma Concentration-time Curve Extrapolated to Infinity | AUC0-∞ - Area under the plasma concentration-time curve extrapolated to infinity for levodopa | pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 h post-dose | 
| Emax - Maximum Inhibition of COMT Activity | Emax - Maximum inhibition of Catechol-O-Methyltransferase (COMT) activity | pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 h post-dose | 
| tEmax - Time of Occurrence of Emax |  | pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 h post-dose | 
| AUEC0-24 - Area Under the Effect-time Curve From t=0h to t=24h |  | pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 h post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parkinson's disease (PD), BIA 9-1067, Opicapone