Effect of Food on BIA 5-1058

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to investigate the effect of food on the pharmacokinetic (PK) profile of BIA 5-1058 after a single dose in healthy subjects.

Detailed Description
-----------------
Single-centre, open-label, randomised, single-dose, three-way crossover, three-part study in 54 healthy subjects. Duration of treatment: The study comprised a screening evaluation between 2 and 28 days before the first IMP (Investigational Medicinal Product) administration and 3 treatment periods of approximately 4 days, separated by wash-out periods of at least 7 days. A follow-up visit was performed approximately 7 days after discharge from the last period or early discontinuation. For each subject, the full duration of the participation in the study was approximately 9 weeks.

Official Title
-----------------
Effect of Food on BIA 5-1058 Bioavailability in Healthy Subjects

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: BIA 5-1058


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able and willing to give written informed consent and to comply with the study restrictions; Male or female subjects aged 18 to 45 years, inclusive; Body mass index (BMI) between 18 and 30 kg/m2, inclusive; Healthy as determined by pre-study medical history, physical examination, vital signs, complete neurological examination and 12-lead electrocardiogram (ECG); Negative tests for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus antibodies (HCV Ab) and anti-human immunodeficiency virus antibodies (HIV-1 and HIV-2 Ab) at screening; Clinical laboratory test results clinically acceptable at screening and admission to each treatment period; Negative screen for alcohol and drugs of abuse at screening and admission to each treatment period; Non-smokers or ex-smokers for at least 3 months. If female: No childbearing potential by reason of surgery or at least 1 year post menopause (i.e., 12 months post last menstrual period), or menopause confirmed by follicle-stimulating hormone (FSH) testing; If of childbearing potential, she was using an effective non-hormonal method of contraception [intrauterine device or intrauterine system; condom or occlusive cap (diaphragm or cervical or vault caps) with spermicidal foam or gel or film or cream or suppository; true abstinence; or vasectomized male partner, provided that he is the sole partner of that subject] for all the duration of the study; Negative serum pregnancy test at screening and negative urine pregnancy test on admission of each treatment period (women of childbearing potential only). If male: Using an effective method of contraception with a pregnant partner or partner of childbearing potential (condom or occlusive cap [diaphragm or cervical or vault caps] with spermicidal foam or gel or film or cream or suppository; true abstinence; or vasectomy) throughout the study; Refraining from donating sperm throughout the study. Exclusion Criteria: 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; Clinically relevant surgical history; History of relevant atopy or drug hypersensitivity; History of alcoholism or drug abuse; Consumption of more than 14 units of alcohol a week [1 glass (25 cL) of beer with 3° of alcohol = 7.5 g, or 1 glass (25 cL) of beer with 6° of alcohol = 15 g, or 1 glass (12.5 cL) of wine with 10° of alcohol = 12 g, or 1 glass (4cL) of aperitif with 42° of alcohol = 17 g]; Significant infection or known inflammatory process at screening or admission to each treatment period; Display of acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission to each treatment period; Use of medicines within 2 weeks of admission to the first period that may could affect the safety or other study assessments, in the Investigator's opinion; Previous administration of BIA 5-1058; Use of any investigational drug or participation in any clinical trial within 90 days prior to screening; Participation in more than 2 clinical trials within the 12 months prior to screening; Donation or reception of any blood or blood products within the 3 months prior to screening; Vegetarians, vegans or had any other medical dietary restrictions; Not able to communicate reliably with the Investigator; Unlikely to co-operate with the requirements of the study. If female: Pregnant or breastfeeding; Not using an accepted effective contraceptive method or was using oral contraceptives. If male: Not using an accepted effective method of contraception; Refusing to refrain from donating sperm throughout the study.

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

Sexes Eligible for Study
-----------------
All

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PART 1 (400 mg BIA 5-1058)<br>Each subject was orally administered a single oral dose of BIA 5-1058 on D1 (dosing day) on three different occasions (Period 1, Period 2 and Period 3): Part 1: 400 mg BIA 5-1058 as four (4) 100 mg tablets in Period 1, 400 mg BIA 5-1058 as four (4) 100 mg tablets in Period 2, and 400 mg BIA 5-1058 as four (4) 100 mg tablets in Period 3. | Drug: BIA 5-1058<br>* BIA 5-1058 (tablets 100 mg) was administered orally with 240 mL (Part 1) or 270 mL (Part 2 and Part 3) of water, in one period in the morning under fasting conditions (after at least a 10-hour overnight fast), in one period in the morning after a moderate meal, and in the other period at lunch after a moderate meal.<br>* Other names: Zamicastat;|
| Experimental: PART 2 (800 mg BIA 5-1058)<br>Each subject was orally administered a single oral dose of BIA 5-1058 on D1 (dosing day) on three different occasions (Period 1, Period 2 and Period 3): Part 2: 800 mg BIA 5-1058 as eight (8) 100 mg tablets in Period 1, 800 mg BIA 5-1058 as eight (8) 100 mg tablets in Period 2, and 800 mg BIA 5-1058 as eight (8) 100 mg tablets in Period 3. | Drug: BIA 5-1058<br>* BIA 5-1058 (tablets 100 mg) was administered orally with 240 mL (Part 1) or 270 mL (Part 2 and Part 3) of water, in one period in the morning under fasting conditions (after at least a 10-hour overnight fast), in one period in the morning after a moderate meal, and in the other period at lunch after a moderate meal.<br>* Other names: Zamicastat;|
| Experimental: PART 3 (1200 mg BIA 5-1058)<br>Each subject was orally administered a single oral dose of BIA 5-1058 on D1 (dosing day) on three different occasions (Period 1, Period 2 and Period 3): Part 3: 1200 mg BIA 5-1058 as twelve (12) 100 mg tablets in Period 1, 1200 mg BIA 5-1058 as twelve (12) 100 mg tablets in Period 2, and 1200 mg BIA 5-1058 as twelve (12) 100 mg tablets in Period 3. | Drug: BIA 5-1058<br>* BIA 5-1058 (tablets 100 mg) was administered orally with 240 mL (Part 1) or 270 mL (Part 2 and Part 3) of water, in one period in the morning under fasting conditions (after at least a 10-hour overnight fast), in one period in the morning after a moderate meal, and in the other period at lunch after a moderate meal.<br>* Other names: Zamicastat;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) | In all treatment periods, blood samples were taken at the following times: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose | Up to 9 weeks | 
| Time of occurrence of Cmax (tmax) | In all treatment periods, blood samples were taken at the following times: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose | Up to 9 weeks | 
| Area under the plasma concentration-time curve (AUC) | In all treatment periods, blood samples were taken at the following times: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose | Up to 9 weeks | 
| Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which the drug concentration was at or above the lower limit of quantification (AUC0-last) | In all treatment periods, blood samples were taken at the following times: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose | Up to 9 weeks |