Hypertension and Chronic Heart Failure
Conditions
Keywords
BIA 5-1058, hypertension, chronic heart failure, cardiovascular disorders
Brief summary
The purpose of this study is to to assess the safety and tolerability of BIA 5 1058 after single and multiple oral doses
Detailed description
This was a Phase 1, double blind, randomised, placebo-controlled combined single ascending dose (SAD), including food interaction (food effect, FE) analysis, and multiple ascending dose (MAD) study. SAD: This part consisted of an eligibility screening period, one study period involving administration of single doses of BIA 5-1058 or placebo according to a randomized design, and a follow-up period. Nine sequential groups of 8 healthy young male subjects were dosed. Within each group, 6 subjects were randomised to receive BIA 5-1058 and 2 subjects were randomised to receive placebo. In this first-in-human study, the subjects participating at the lowest dose level of 5 mg were dosed according to a sentinel dosing design to ensure optimal safety. Initially, 2 subjects were dosed; 1 subject with BIA 5-1058 and 1 subject with placebo. After the safety and tolerability results of the first 24 h following dosing for the initial subjects had been found to be acceptable to the MI, the other 6 subjects of the lowest dose level were dosed. MAD: This part consisted of an eligibility screening period, one study period involving administration of multiple doses of BIA 5-1058 or placebo once daily for 10 days, and a follow-up period. Five sequential groups of 8 healthy young male subjects were dosed. Within each group, 6 subjects were randomised to receive BIA 5-1058 and 2 subjects were randomised to receive placebo. The starting dose of 50 mg was chosen taking into consideration the dose range of the previous SAD sequential groups and was approved by the IEC. Escalation to the next higher dose and the determination of the next dose level was based on safety, tolerability and available PK results of the previously administered dose FE: This part consisted of an eligibility screening period, an open-label two-way crossover study period, and a follow-up period. One group of 12 subjects received single doses of 400 mg BIA 5-1058 during 2 treatment periods, once after having fasted overnight and once after consumption of a high fat breakfast. Each treatment was separated by a period of at least 7 days. The treatment sequence was determined by randomisation.
Interventions
DRUGBIA 5-1058
oral administration
DRUGPlacebo
oral administration
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects were eligible for the study if they met all the following inclusion criteria: * Gender - male * Age - 18 - 55 years, inclusive * Body Mass Index (BMI) - 18.0 - 30.0 kg m2 (BMI (kg m2) = Body weight (kg) - Heigh t2 (m 2)) * Ability and willingness to abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, power drinks), grapefruit (juice) and tobacco products from 48 h prior to entry in the clinical research centre until discharge * Medical history without major pathology * Normal resting supine blood pressure and pulse rate showing no clinically relevant deviations as judged by the MI * Computerised (12-lead) ECG recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the MI * All values for haematology and for clinical chemistry tests of blood and urine within the normal range or showing no clinically relevant deviations as judged by the MI * Willingness to sign the written ICF
Exclusion criteria
Subjects were excluded from participation if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | Just before drug administration and twice daily until 72 h after (last) drug administration | Just before drug administration and twice daily until 72 h after (last) drug administration, subjects were asked non-leading questions to determine the occurrence of AEs. Subjects were asked in general terms about any AEs at regular intervals during each study period. In addition, all AEs reported spontaneously during the course of the study were recorded. All answers were assessed by the Medical Investigator (MI), coded using the Medical Dictionary for Regulatory Activities (MedDRA; Version 14.0) and recorded in the AEs Record. The intensity of the AEs was rated as mild, moderate or severe and the relationship between the AEs and the study medication was indicated as not related, unlikely, possible, probable or ''definite. |
| Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period | Just before drug administration and twice daily until 72 h after (last) drug administration | Just before drug administration and twice daily until 72 h after (last) drug administration, subjects were asked non-leading questions to determine the occurrence of AEs. Subjects were asked in general terms about any AEs at regular intervals during each study period. In addition, all AEs reported spontaneously during the course of the study were recorded. All answers were assessed by the Medical Investigator (MI), coded using the Medical Dictionary for Regulatory Activities (MedDRA; Version 14.0) and recorded in the AEs Record. The intensity of the AEs was rated as mild, moderate or severe and the relationship between the AEs and the study medication was indicated as not related, unlikely, possible, probable or ''definite. |
| Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Food Effect (FE) | Just before drug administration and twice daily until 72 h after (last) drug administration | Just before drug administration and twice daily until 72 h after (last) drug administration, subjects were asked non-leading questions to determine the occurrence of AEs. Subjects were asked in general terms about any AEs at regular intervals during each study period. In addition, all AEs reported spontaneously during the course of the study were recorded. All answers were assessed by the Medical Investigator (MI), coded using the Medical Dictionary for Regulatory Activities (MedDRA; Version 14.0) and recorded in the AEs Record. The intensity of the AEs was rated as mild, moderate or severe and the relationship between the AEs and the study medication was indicated as not related, unlikely, possible, probable or ''definite. |
Countries
Netherlands
Participant flow
Recruitment details
Study period : Date of first screening to last follow-up: 03 March 2011 - 13 January 2012;
Participants by arm
| Arm | Count |
|---|---|
| Single Ascending Dose (SAD) This part consisted of an eligibility screening period, one study period involving administration of single doses of BIA 5-1058 or placebo according to a randomised design, and a follow-up period. Nine sequential groups of 8 healthy young male subjects were dosed. Within each group, 6 subjects were randomised to receive BIA 5-1058 and 2 subjects were randomised to receive placebo. | 72 |
| Multiple Ascending Dose (MAD) This part consisted of an eligibility screening period, one study period involving administration of multiple doses of BIA 5-1058 or placebo once daily for 10 days, and a follow-up period. Five sequential groups of 8 healthy young male subjects were dosed. Within each group, 6 subjects were randomised to receive BIA 5-1058 and 2 subjects were randomised to receive placebo. | 40 |
| Food Interaction (Food Effect, FE) Analysis This part consisted of an eligibility screening period, an open-label two-way crossover study period, and a follow-up period. One group of 12 subjects received single doses of 400 mg BIA 5-1058 during 2 treatment periods, once after having fasted overnight and once after consumption of a high fat breakfast. Each treatment was separated by a period of at least 7 days. The treatment sequence was determined by randomisation. | 12 |
| Total | 124 |
Baseline characteristics
| Characteristic | Single Ascending Dose (SAD) | Multiple Ascending Dose (MAD) | Food Interaction (Food Effect, FE) Analysis | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 72 Participants | 38 Participants | 12 Participants | 122 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 72 Participants | 40 Participants | 12 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 18 | 0 / 6 | 2 / 6 | 3 / 6 | 2 / 6 | 4 / 6 | 4 / 6 | 3 / 6 | 1 / 6 | 4 / 6 | 3 / 12 | 5 / 12 | 8 / 10 | 5 / 6 | 3 / 6 | 5 / 6 | 3 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 18 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 12 | 0 / 10 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Food Effect (FE)
Just before drug administration and twice daily until 72 h after (last) drug administration, subjects were asked non-leading questions to determine the occurrence of AEs. Subjects were asked in general terms about any AEs at regular intervals during each study period. In addition, all AEs reported spontaneously during the course of the study were recorded. All answers were assessed by the Medical Investigator (MI), coded using the Medical Dictionary for Regulatory Activities (MedDRA; Version 14.0) and recorded in the AEs Record. The intensity of the AEs was rated as mild, moderate or severe and the relationship between the AEs and the study medication was indicated as not related, unlikely, possible, probable or ''definite.
Time frame: Just before drug administration and twice daily until 72 h after (last) drug administration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Food Effect (FE) | 0 % of subject with TEAEs related to SM |
| 5 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Food Effect (FE) | 17 % of subject with TEAEs related to SM |
Primary
Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period
Just before drug administration and twice daily until 72 h after (last) drug administration, subjects were asked non-leading questions to determine the occurrence of AEs. Subjects were asked in general terms about any AEs at regular intervals during each study period. In addition, all AEs reported spontaneously during the course of the study were recorded. All answers were assessed by the Medical Investigator (MI), coded using the Medical Dictionary for Regulatory Activities (MedDRA; Version 14.0) and recorded in the AEs Record. The intensity of the AEs was rated as mild, moderate or severe and the relationship between the AEs and the study medication was indicated as not related, unlikely, possible, probable or ''definite.
Time frame: Just before drug administration and twice daily until 72 h after (last) drug administration
Population: No drug-related TEAEs were reported for the dose levels of 50 mg md and 400 mg md.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period | 30 % of subject with TEAEs related to SM |
| 5 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period | 0 % of subject with TEAEs related to SM |
| 25 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period | 50 % of subject with TEAEs related to SM |
| 50 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period | 33 % of subject with TEAEs related to SM |
| 100 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period | 0 % of subject with TEAEs related to SM |
| 200 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Multiple Ascending Dose (MAD) Period | 33 % of subject with TEAEs related to SM |
Primary
Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period
Just before drug administration and twice daily until 72 h after (last) drug administration, subjects were asked non-leading questions to determine the occurrence of AEs. Subjects were asked in general terms about any AEs at regular intervals during each study period. In addition, all AEs reported spontaneously during the course of the study were recorded. All answers were assessed by the Medical Investigator (MI), coded using the Medical Dictionary for Regulatory Activities (MedDRA; Version 14.0) and recorded in the AEs Record. The intensity of the AEs was rated as mild, moderate or severe and the relationship between the AEs and the study medication was indicated as not related, unlikely, possible, probable or ''definite.
Time frame: Just before drug administration and twice daily until 72 h after (last) drug administration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 28 % of subject with TEAEs related to SM |
| 5 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 0 % of subject with TEAEs related to SM |
| 25 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 0 % of subject with TEAEs related to SM |
| 50 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 0 % of subject with TEAEs related to SM |
| 100 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 0 % of subject with TEAEs related to SM |
| 200 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 0 % of subject with TEAEs related to SM |
| 400 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 17 % of subject with TEAEs related to SM |
| 800 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 17 % of subject with TEAEs related to SM |
| 1600 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 0 % of subject with TEAEs related to SM |
| 2400 mg | Percentage (%) of Subjects With Treatment-Emergent Adverse Event (TEAE) Related to Study Medication (SM) - Single Ascending Dose (SAD) Period | 67 % of subject with TEAEs related to SM |