Epilepsy
Conditions
Brief summary
Open-label study in two parallel groups of 20 healthy subjects each. Group A assessed the effect of CBZ on ESL pharmacokinetics, and Group B assessed the effect of ESL on CBZ pharmacokinetics.
Detailed description
Open-label study in two parallel groups of 20 healthy subjects each. Group A assessed the effect of CBZ on ESL pharmacokinetics, and Group B assessed the effect of ESL on CBZ pharmacokinetics. Each patient participated in the study for approximately 9 weeks. The clinical portion of the study was completed in approximately 3 months. Subjects received the treatments during 35 days.
Interventions
DRUGBIA 2-093
DRUGCarbamazepine
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Male and 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, and 12-lead electrocardiogram (ECG); negative tests for Hepatitis B surface Antigen (HBsAg), anti-HCVAb and Human Immunodeficiency Virus (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; * Able and willing to give written informed consent; * If female, not of childbearing potential by reason of surgery or, if of childbearing potential, she used a double-barrier method of contraception: 1 male barrier method \[male condom\] plus 1 female barrier method (diaphragm, spermicide, or intrauterine device); * If female, had a negative urine pregnancy test at screening and admission to each treatment period.
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; have a clinically relevant surgical history; * History of relevant atopy or any drug hypersensitivity (including known hypersensitivity to ESL or other carboxamide derivatives \[e.g., carbamazepine, oxcarbazepine\] or any of its excipients; known hypersensitivity to drugs structurally related to carbamazepine \[e.g.: tricyclic antidepressants\] or any of its excipients); * Second or third-degree atrioventricular blockade not corrected with a pace-maker or any other clinically significant abnormality in the 12-lead ECG as determined by the investigator; * History of alcoholism or drug abuse; * Consumed more than 14 units1 of alcohol a week; * Significant infection or known inflammatory process on screening or admission to each treatment period; * Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission to each treatment period; * Use of medicines within two weeks of admission to first period that may affect the safety or other study assessments, in the investigator's opinion; * Had donated or received any blood or blood products within the 3 months prior to screening; * Vegetarians, vegans or have other medical dietary restrictions; * Could not communicate reliably with the investigator; was unlikely to co-operate with the requirements of the study; * Unwilling or unable to give written informed consent; * If female, was pregnant or breast-feeding; * If female, was of childbearing potential and did not use an accepted effective contraceptive method or used hormonal contraceptives; * Had received an investigational drug within 3 months of screening or was currently participating in another study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax (BIA 2-093) - the Maximum Plasma Concentration | Day 7 to 35 | Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg |
| Cmax (CBZ) - the Maximum Plasma Concentration | Day 28 to 35 | Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg |
| Cmax (CBZE) - the Maximum Plasma Concentration | Day 28 to 35 | Reference - Day 28 following twice-daily oral administration of CBZ 400 mg twice-daily Test - Day 35 following twice-daily oral administration of CBZ 400 mg twice-daily CBZE - carbamazepine-epoxide is the active metabolite of CBZ |
| AUC0-t (BIA 2-093) - Area Under the Curve to Last Measurable Concentration for BIA 2-093 | Day 7 to 35 | Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg |
| AUC0-t (CBZ) - Area Under the Curve to Last Measurable Concentration for CBZ | Day 28 to 35 | Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg |
| AUC0-t (CBZE) - Area Under the Curve to Last Measurable Concentration for CBZE | Day 28 to 35 | Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg CBZE - carbamazepine-epoxide is the active metabolite of CBZ |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A Day 1 to Day 8 - BIA 2-093 800 mg Day 9 to Day 14 - BIA 2-093 800 mg + CBZ 200 mg Day 15 to Day 22 - BIA 2-093 800 mg + CBZ 400 mg Day 23 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily | 23 |
| Group B Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + 400 mg twice-daily | 20 |
| Total | 43 |
Baseline characteristics
| Characteristic | Group A | Group B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 20 Participants | 43 Participants |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 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 |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 20 | 9 / 20 | 12 / 20 | 21 / 39 | 14 / 23 | 10 / 21 | 10 / 19 | 0 / 43 | 4 / 38 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 39 | 0 / 23 | 0 / 21 | 0 / 19 | 0 / 43 | 0 / 38 |
Outcome results
Primary
AUC0-t (BIA 2-093) - Area Under the Curve to Last Measurable Concentration for BIA 2-093
Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg
Time frame: Day 7 to 35
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | AUC0-t (BIA 2-093) - Area Under the Curve to Last Measurable Concentration for BIA 2-093 | AUC0-t ESL (D35 ESL 800mg) | 188648 ng*h/mL | Standard Deviation 23897 |
| Group A | AUC0-t (BIA 2-093) - Area Under the Curve to Last Measurable Concentration for BIA 2-093 | AUC0-t ESL (D7 ESL 800mg) | 276836 ng*h/mL | Standard Deviation 43062 |
Primary
AUC0-t (CBZ) - Area Under the Curve to Last Measurable Concentration for CBZ
Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg
Time frame: Day 28 to 35
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | AUC0-t (CBZ) - Area Under the Curve to Last Measurable Concentration for CBZ | AUC0-t CBZ (D28 CBZ 400 mg twice-daily) | 104494 ng*h/mL | Standard Deviation 16344 |
| Group A | AUC0-t (CBZ) - Area Under the Curve to Last Measurable Concentration for CBZ | AUC0-t CBZ (D35 CBZ 400 mg twice-daily) | 94394 ng*h/mL | Standard Deviation 17230 |
Primary
AUC0-t (CBZE) - Area Under the Curve to Last Measurable Concentration for CBZE
Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg CBZE - carbamazepine-epoxide is the active metabolite of CBZ
Time frame: Day 28 to 35
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | AUC0-t (CBZE) - Area Under the Curve to Last Measurable Concentration for CBZE | AUC0-t CBZE (D28 CBZ 400 mg twice-daily) | 15322 ng*h/mL | Standard Deviation 3857 |
| Group A | AUC0-t (CBZE) - Area Under the Curve to Last Measurable Concentration for CBZE | AUC0-t CBZE (D35 CBZ 400 mg twice-daily) | 14953 ng*h/mL | Standard Deviation 3121 |
Primary
Cmax (BIA 2-093) - the Maximum Plasma Concentration
Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg
Time frame: Day 7 to 35
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Cmax (BIA 2-093) - the Maximum Plasma Concentration | Cmax ESL (D7 ESL 800mg) | 18601 ng/mL | Standard Deviation 3164 |
| Group A | Cmax (BIA 2-093) - the Maximum Plasma Concentration | Cmax ESL (D35 ESL 800mg) | 14591 ng/mL | Standard Deviation 1800 |
Primary
Cmax (CBZE) - the Maximum Plasma Concentration
Reference - Day 28 following twice-daily oral administration of CBZ 400 mg twice-daily Test - Day 35 following twice-daily oral administration of CBZ 400 mg twice-daily CBZE - carbamazepine-epoxide is the active metabolite of CBZ
Time frame: Day 28 to 35
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Cmax (CBZE) - the Maximum Plasma Concentration | Cmax CBZE (D28 CBZ 400 mg twice-daily) | 1562 ng/mL | Standard Deviation 429 |
| Group A | Cmax (CBZE) - the Maximum Plasma Concentration | Cmax CBZE (D35 CBZ 400 mg twice-daily) | 1560 ng/mL | Standard Deviation 332 |
Primary
Cmax (CBZ) - the Maximum Plasma Concentration
Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg
Time frame: Day 28 to 35
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A | Cmax (CBZ) - the Maximum Plasma Concentration | Cmax CBZ (D35 CBZ 400 mg twice-daily) | 9719 ng/mL | Standard Deviation 2019 |
| Group A | Cmax (CBZ) - the Maximum Plasma Concentration | Cmax CBZ (D28 CBZ 400 mg twice-daily) | 10414 ng/mL | Standard Deviation 1896 |