Tolerability, Pharmacokinetics and Dopamine ß-hydroxylase (DßH) Inhibition Profile of BIA 5-453

Phase 1

Completed

• Conditions: Chronic Heart Failure; Hypertension
• Interventions: Drug: BIA 5-453; Drug: Placebo

• Registration Number: NCT02845037
• Lead Sponsor: Bial - Portela C S.A.

Brief Summary

The purpose of this study is to assess the safety and tolerability of BIA 5-453 after single oral doses

Detailed Description

Single centre, randomised, double-blind, placebo-controlled study of single ascending doses in 10 sequential groups of 8 healthy young male volunteers. Within each group (n=8), 6 volunteers were randomised to receive BIA 5-453 and the remaining 2 volunteers were randomised to receive placebo. A volunteer participated only in a single period.

Study Timeline

• Study Start: 2007-05
• Primary Completion: 2007-09
• Study Completion: 2007-09
• Status Verified: 2016-07
• Study First Submitted: 2016-07-15
• Study First Submitted QC: 2016-07-22
• Last Update Submitted: 2016-07-22
• Study First Posted: 2016-07-26
• Last Update Posted: 2016-07-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 80

Inclusion Criteria

1. A signed and dated informed consent form before any study-specific screening procedure was performed.
2. Aged between 18 and 45 years, inclusive.
3. Healthy as determined by the investigator on the basis of medical history, physical examination, clinical laboratory test results, vital signs and digital 12-lead electrocardiogram (ECG).
4. Nonsmoker or smoker of fewer than 10 cigarettes per day as determined by history. Must have been able to abstain from smoking during the inpatient stay.
5. Have a high probability for compliance with and completion of the study.

Exclusion Criteria

Medical History

1. 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.

2. Acute disease state (e.g., nausea, vomiting, fever, diarrhoea) within 7 days before study day 1.

3. History of drug abuse within 1 year before study day 1.

4. 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

5. History of any clinically important drug allergy.

   Physical and Laboratory Findings

6. An automatic ECG QTc interval reading at screening or enrolment >450 ms.

7. Positive serologic findings for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibodies.

8. Positive findings of urine drug screen (eg, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, MDMA [3,4-methylenedioxy-methamphetamine; ecstasy]).

   Prohibited treatments

9. Prohibited Treatments: use of any investigational drug within 90 days or prescription drug within 30 days before investigational medical product (IMP) administration.

10. Consumption of any caffeine-containing products (e.g., coffee, tea, chocolate, or soda) in excess of 6 cups per day (or equivalent), of grapefruit, grapefruit-containing products, or alcoholic beverages within 72 before study day -1.

11. Use of any over-the-counter drugs including herbal supplements (except for the occasional use of acetaminophen [paracetamol], aspirin and vitamins ≤100% recommended daily allowance) within 7 days before IMP administration.

12. Donation of blood (ie 450 ml) within 90 days before study day 1.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
100 mg or placebo	BIA 5-453	BIA 5-453 or placebo
200 mg or placebo	BIA 5-453	BIA 5-453 or placebo
600 mg or placebo	BIA 5-453	BIA 5-453 or placebo
1200 mg or placebo	BIA 5-453	BIA 5-453 or placebo
100 mg or placebo	Placebo	BIA 5-453 or placebo
1200 mg or placebo	Placebo	BIA 5-453 or placebo
2 mg or placebo	BIA 5-453	BIA 5-453 or placebo
20 mg or placebo	Placebo	BIA 5-453 or placebo
900 mg or placebo	BIA 5-453	BIA 5-453 or placebo
2 mg or placebo	Placebo	BIA 5-453 or placebo
20 mg or placebo	BIA 5-453	BIA 5-453 or placebo
50 mg or placebo	BIA 5-453	BIA 5-453 or placebo
600 mg or placebo	Placebo	BIA 5-453 or placebo
10 mg or placebo	BIA 5-453	BIA 5-453 or placebo
200 mg or placebo	Placebo	BIA 5-453 or placebo
400 mg or placebo	Placebo	BIA 5-453 or placebo
10 mg or placebo	Placebo	BIA 5-453 or placebo
50 mg or placebo	Placebo	BIA 5-453 or placebo
400 mg or placebo	BIA 5-453	BIA 5-453 or placebo
900 mg or placebo	Placebo	BIA 5-453 or placebo

Primary Outcome Measures

Name	Time	Method
% of subjects with at least one adverse event	through study completion, an average of 72 hours	Adverse events were continuously monitored from screening until the follow-up visit.
Time to reach Cmax (Tmax)	Day 1 pre-dose then at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 72 hours post-dose	Mean BIA 5-453 plasma pharmacokinetic parameters ± SD following single doses of 2, 10, 20, 50, 100, 200, 400, 600, 900 and 1200 mg of BIA 5-453 in 10 groups of 6 healthy volunteers each
Area under the plasma concentration-time curve from time 0 to the infinity (AUC0-∞)	Day 1 pre-dose then at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 72 hours post-dose	Mean BIA 5-453 plasma pharmacokinetic parameters ± SD following single doses of 2, 10, 20, 50, 100, 200, 400, 600, 900 and 1200 mg of BIA 5-453 in 10 groups of 6 healthy volunteers each
Maximum observed plasma concentration (Cmax)	Day 1 pre-dose then at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 72 hours post-dose	Mean BIA 5-453 plasma pharmacokinetic parameters ± SD following single doses of 2, 10, 20, 50, 100, 200, 400, 600, 900 and 1200 mg of BIA 5-453 in 10 groups of 6 healthy volunteers each
Area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration (AUC0-t)	Day 1 pre-dose then at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 72 hours post-dose	Mean BIA 5-453 plasma pharmacokinetic parameters ± SD following single doses of 2, 10, 20, 50, 100, 200, 400, 600, 900 and 1200 mg of BIA 5-453 in 10 groups of 6 healthy volunteers each
% of subjects by dose group with at least one treatment-emergent adverse event (TEAEs)	through study completion, an average of 72 hours	Treatment emergent adverse events (TEAE) were defined as adverse events which did not exist before dosing and appeared in the 72 hours following treatment administration or which was present before administration and worsened in the 72 hours following treatment administration.
Apparent terminal elimination half-life (t1/2)	Day 1 pre-dose then at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 72 hours post-dose	Mean BIA 5-453 plasma pharmacokinetic parameters ± SD following single doses of 2, 10, 20, 50, 100, 200, 400, 600, 900 and 1200 mg of BIA 5-453 in 10 groups of 6 healthy volunteers each

Trial Locations

Locations (1)

Biotrial; 🇫🇷 Rennes, France