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

Pulmonary Arterial Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03708146
• Other study ID #: BIA-51058-116
• Secondary ID: 2018-000113-20
• Status: Completed
• Phase: Phase 1
• Start date: May 28, 2018
• Est. completion date: March 18, 2019

Study information

• Verified date: December 2020
• Source: Bial - Portela C S.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 157
• Est. completion date: March 18, 2019
• Est. primary completion date: March 18, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cardiovascular Disease+Pulmonary Disease
• Cardiovascular Diseases
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

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.
• 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.

Locations

Country	Name	City	State
United Kingdom	Quotient Sciences	Ruddington	Nottingham

Sponsors (1)

Lead Sponsor	Collaborator
Bial - Portela C S.A.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cmax: maximum observed concentration	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	Cmin: minimum observed concentration at steady state	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	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
Primary	Tmax: the time from dosing at which Cmax was apparent	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	AUC(0-t): area under the curve from 0 time to last measurable concentration	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	AUC(0-tau): area under the curve during a dosing interval	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	AUC(0-inf): area under the curve from 0 time extrapolated to infinity	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	AUC%extrap: percentage of AUC(0-inf) extrapolated beyond last measured time point	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	Lambda-z: the slope of the apparent elimination phase	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	t1/2: the apparent elimination half-life	PK parameters analysis	Day 1, Day 6 and Day 10
Primary	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
Primary	MRT: mean residence time	PK parameters analysis	Day 1, Day 6 and Day 10
Secondary	Emax: maximum observed % change from time-matched baseline	Pharmacodynamic parameters analysis	Day 1 and Day 10
Secondary	TEmax: Time of maximum observed % change from time-matched baseline	Pharmacodynamic parameters analysis	Day 1 and Day 10
Secondary	EAUC: % change from time-matched baseline area under the curve during a dosing interval	Pharmacodynamic parameters analysis	Day 1 and Day 10
Secondary	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
Secondary	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
Secondary	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
Secondary	% inhibition of dopamine ß-hydroxylase (DßH) activity		Day 1 and Day 10