Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BIA 5-1058

A Double-Blind, Randomised, Placebo-Controlled, Parallel Group Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Doses of BIA 5 1058 in Healthy Volunteers

This is a single centre, double-blind, randomised, placebo-controlled, parallel staggered group study of BIA 5-1058 in 11 different cohorts of 15 healthy subjects. Subjects will be randomly assigned to receive once-daily oral doses of BIA 5-1058 or matching placebo for 10 days.

The primary objectives of the study are to assess the safety and tolerability of BIA 5-1058 after repeated ascending doses under fed and fasted conditions and to assess the pharmacokinetics (PK) of BIA 5-1058 after repeated ascending doses under fed conditions having matching fasting cohorts for comparison of bioavailability.

It is planned that comparison cohorts will be dosed in parallel, i.e. Cohorts 1 and 2, 3 and 4, 5 and 6, 7 and 8 and 9 and 10. Cohorts may be split or dosed sequentially for logistical purposes; however, data from both comparison cohorts (e.g. Cohorts 1 and 2) must be available before dose escalation to the next dose levels.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Cardiovascular Disease+Pulmonary Disease
• Intervention / Treatment: Drug: BIA 5-1058; Drug: Placebo

Detailed Description

Each cohort will follow the same study design. Subjects will be screened for inclusion in the study between 28 and 3 days before the first dose. Eligible subjects will be admitted 2 days before dosing (Day -2) for all regimens, and will remain resident in the clinic until 72 h after the last dose (Day 13). On Day -1, blood samples will be taken in all cohorts for PD assessments at pre-defined time points. These time points will be time matched to Day 1 PK and PD time points. Subjects in Cohorts 2, 4, 6, 8, 10 and 11 (fed cohorts) will also undergo continuous cardiac monitoring via 24 h Holter recordings on Day -1.

Subjects in Cohorts 1, 3, 5, 7 and 9 will receive oral doses of BIA 5-1058 or matching placebo once daily from Day 1 to Day 10, administered in the morning of each day after a minimum of 8 h fast and will remain fasted until 4 h post-dose. Subjects in Cohorts 2, 4, 6, 8, 10 and 11 will receive oral doses of BIA 5-1058 or matching placebo once daily from Day 1 to Day 10, administered in the morning of each day, 30 minutes after the start of a moderate breakfast containing approximately 550 kcal with fat contributing approximately 150 kcal.

• Study Type: Interventional
• Enrollment (Actual): 157
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham
    • Ruddington, Nottingham, United Kingdom, NG11 6JS
      • Quotient Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Able and willing to comply with the study restrictions and to give written informed consent before any study procedure; Male or non-pregnant, non-lactating female subjects aged 18 to 55 years, inclusive; Body mass index (BMI) between 18.0 and 32.0 kg/m2 or, if outside the range, considered not clinically significant by the investigator; Healthy as determined by the investigator based on medical history, physical examination, clinical laboratory test results, vital signs (systolic blood pressure ≥ 90 mmHg and ≤ 150 mmHg, diastolic blood pressure ≥ 50 mmHg and ≤ 90 mmHg) and digital 12-lead 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 Negative screen for alcohol and drugs of abuse at screening and admission Non-smokers or ex-smokers for at least 3 months;

Must adhere to the contraception requirements:

Male subjects and female partner willing to a condom plus an approved method of effective contraception, if applicable (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from the time of informed consent until 90 days after last dose of IMP. Male subjects must refrain from donating sperm throughout the study and for 90 days after the last dose of IMP; Female subjects of childbearing potential willing to use, with their partner, a condom and an approved method of highly effective contraception from the time of informed consent until 30 days after the last follow-up visit. Hormonal contraceptives are not permitted for female subjects. Female subjects must not donate ova from the time of the first dose until 90 days after the last dose of study drug; If female, nonchildbearing 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 Negative serum pregnancy test at screening and negative urine pregnancy test on admission (all female subjects).

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 based on medical judgement by the investigator, excluding, for example, simple appendectomy or herniorrhaphy; Estimated glomerular filtration rate < 70 mL/min History of drug hypersensitivity or a presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active; Clinically relevant history of alcoholism or drug abuse in the past 5 years; Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type); Current smokers and those who have smoked within the last 3 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission; Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 3 months; Significant infection or known inflammatory process at screening or admission; Abnormal fundoscopy result at screening; Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission; Use of over the counter medications (including oral natural health products, vitamin and herbal supplements) in the 7 days before the first dose of IMP and use of prescription medications that may affect the safety or other study assessments, in the PI's opinion, are not permitted within 14 days before the first dose of IMP. By exception, acetaminophen/paracetamol ≤ 1 g/day is permitted. Other exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor; Subjects who have previously been enrolled in a BIA 5-1058 study or who have previously been enrolled and dosed in this study; Use of any investigational drug or participation in any clinical trial within 90 days prior to screening; Donation or reception of any blood or blood products within the 3 months prior to screening; Donation or loss of greater than 400 mL of blood within the previous 3 months; Vegetarians, vegans or other medical dietary restrictions; Subjects with a history of cholecystectomy or gall stones; Not able to communicate reliably with the investigator or sub-investigator; Unlikely to co-operate with the requirements of the study; Subjects who are study site employees, or immediate family members of a study site or sponsor employee; Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening; Females of childbearing potential who are pregnant or lactating (all female subjects must have a negative serum pregnancy test at screening and a negative urine pregnancy test at admission); Males with pregnant partners; Failure to satisfy the investigator of fitness to participate for any other reason; Are unwilling or unable to give written informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (BIA 5-1058 /50 mg/fasted); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 50 mg (as 2 x 25 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 2 (BIA 5-1058 /25 mg/fed); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 25 mg (as 1 x 25 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 3 (BIA 5-1058 /100 mg/fasted); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 100 mg (as 1 x 100 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 4 (BIA 5-1058 /50 mg/fed); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 50 mg (as 2 x 25 mg tablet) or matching placebo 12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 5 (BIA 5-1058 /150 mg/fasted); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 150 mg (as 1 x 100 mg and 2 x 25 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 6 (BIA 5-1058 /75 mg/fed); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 75 mg (as 3 x 25 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 7 (BIA 5-1058 /200 mg/fasted); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 200 mg (as 2 x 100 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 8 (BIA 5-1058 /100 mg/fed); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 100 mg (as 1 x 100 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 9 (BIA 5-1058 /400 mg/fasted); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 400 mg (as 4 x 100 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 10 (BIA 5-1058 /200 mg/fed); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 200 mg (as 2 x 100 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.
Experimental: Cohort 11 (BIA 5-1058 /400 mg/fed); 15 Subjects: 12 active and 3 placebo; BIA 5-1058 Tablet 400 mg (as 4 x 100 mg tablet) or matching placebo tablet (12 active and 3 placebo)	Drug: BIA 5-1058; 25 mg and 100 mg tablets; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), BIA 5-1058 will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), BIA 5-1058 will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.; Other Names: Zamicastat; Drug: Placebo; matching placebo tablet; Oral, once-daily, from Day 1 to Day 10. In Cohorts 1, 3, 5, 7 and 9 (fasted), placebo will be orally administered in the morning after a minimum of 8 h fast. Subjects will remain fasted until 4 h post-dose and will receive lunch approximately 4 h after dosing. In Cohorts 2, 4, 6, 8 and 10 (fed), placebo will be orally administered in the morning after a moderate breakfast (containing approximately 550 kcal with fat contributing approximately 150 kcal). The meal should be consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of the meal. Each dose will be administered with 240 mL water.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax: maximum observed concentration	PK parameters analysis	Day 1, Day 6 and Day 10
Cmin: minimum observed concentration at steady state	PK parameters analysis	Day 1, Day 6 and Day 10
Tlag: the elapsed time from dosing at which analyte was first quantifiable in a concentration vs time profile	PK parameters analysis	Day 1, Day 6 and Day 10
Tmax: the time from dosing at which Cmax was apparent	PK parameters analysis	Day 1, Day 6 and Day 10
AUC(0-t): area under the curve from 0 time to last measurable concentration	PK parameters analysis	Day 1, Day 6 and Day 10
AUC(0-tau): area under the curve during a dosing interval	PK parameters analysis	Day 1, Day 6 and Day 10
AUC(0-inf): area under the curve from 0 time extrapolated to infinity	PK parameters analysis	Day 1, Day 6 and Day 10
AUC%extrap: percentage of AUC(0-inf) extrapolated beyond last measured time point	PK parameters analysis	Day 1, Day 6 and Day 10
Lambda-z: the slope of the apparent elimination phase	PK parameters analysis	Day 1, Day 6 and Day 10
t1/2: the apparent elimination half-life	PK parameters analysis	Day 1, Day 6 and Day 10
Cl/F: clearance, the apparent volume cleared of parent drug per unit time after extravascular administration	PK parameters analysis	Day 1, Day 6 and Day 10
MRT: mean residence time	PK parameters analysis	Day 1, Day 6 and Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Emax: maximum observed % change from time-matched baseline	Pharmacodynamic parameters analysis	Day 1 and Day 10
TEmax: Time of maximum observed % change from time-matched baseline	Pharmacodynamic parameters analysis	Day 1 and Day 10
EAUC: % change from time-matched baseline area under the curve during a dosing interval	Pharmacodynamic parameters analysis	Day 1 and Day 10
heart rate levels	Change from pre-submersion in heart rate levels following immersion of hand in ice cold water for 4 min (cold pressor test) - Cohort 9 only	pre-dose and Day 10
Blood pressure levels	Change from pre-submersion in , blood pressure levels following immersion of hand in ice cold water for 4 min (cold pressor test) - Cohort 9 only	pre-dose and Day 10
catecholamine (norepinephrine, epinephrine and dopamine) levels	Change from pre-submersion in , catecholamine (norepinephrine, epinephrine and dopamine) levels following immersion of hand in ice cold water for 4 min (cold pressor test) - Cohort 9 only	pre-dose and Day 10
% inhibition of dopamine ß-hydroxylase (DβH) activity		Day 1 and Day 10

Collaborators and Investigators

• Sponsor: Bial - Portela C S.A.

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2018
• Primary Completion (Actual): March 18, 2019
• Study Completion (Actual): March 18, 2019

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: October 12, 2018
• First Posted (Actual): October 17, 2018

Study Record Updates

• Last Update Posted (Actual): December 31, 2020
• Last Update Submitted That Met QC Criteria: December 30, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Cardiovascular Diseases; Pulmonary Arterial Hypertension; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Zamicastat
• Other Study ID Numbers: BIA-51058-116; 2018-000113-20 (EudraCT Number)

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