Epilepsy
Conditions
Brief summary
Single centre, open-label, randomised study in four parallel groups of healthy volunteers
Detailed description
Single centre, open-label, randomised study in four parallel groups of healthy volunteers: Group 1 = 900 mg of eslicarbazepine acetate (ESL, BIA 2-093); Group 2 = 450 mg of S-licarbazepine plus 450 mg of R-licarbazepine; Group 3 = 450 mg of S-licarbazepine; Group 4 = 450 mg of Rlicarbazepine. In each group, the study consisted of a single-dose period (Phase A) followed by a repeateddose period of 7 days of duration in which the investigational product was administered once daily (Phase B). The repeated-dose phase started 96 h post single-dose.
Interventions
DRUGBIA 2-093
Tablets containing 900 mg
DRUGS-licarbazepine
capsules containing 225 mg
DRUGR-licarbazepine
capsules containing 225 mg
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 or female subjects aged between 18 and 45 years, inclusive. * Subjects of body mass index (BMI) between 19 and 30 kg/m2, inclusive. * Subjects who were healthy as determined by pre-study medical history, physical examination, vital signs, neurological examination, and 12-lead ECG. * Subjects who had clinical laboratory tests clinically acceptable at screening and admission. * Subjects who had negative tests for HBsAg, anti-HCV Ab and HIV-1 and HIV-2 Ab at screening. * Subjects who were negative for drugs of abuse and alcohol at screening and admission. * Subjects who were non-smokers or who smoke \< 10 cigarettes or equivalent per day. * Subjects who are able and willing to give written informed consent. * (If female) She was not of childbearing potential by reason of surgery or, if of childbearing potential, she used one of the following methods of contraception: double barrier, intrauterine device or abstinence. * (If female) She had a negative pregnancy test at screening and admission to Phase A.
Exclusion criteria
* Subjects who did not conform to the above inclusion criteria, OR * Subjects who had a 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. * Subjects who had a clinically relevant surgical history. * Subjects who had a clinically relevant family history. * Subjects who had a history of relevant atopy. * Subjects who had a history of relevant drug hypersensitivity (especially carbamazepine or oxcarbazepine). * Subjects who had a history of alcoholism or drug abuse. * Subjects who consumed more than 14 units of alcohol a week. * Subjects who had a significant infection or known inflammatory process on screening or admission.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax - the Maximum Plasma Concentration | Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine. |
| Tmax - the Time of Occurrence of Cmax | Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine. |
| AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eslicarbazepine Acetate 900mg of eslicarbazepine acetate (ESL, BIA 2-093)
BIA 2-093: Tablets containing 900 mg | 8 |
| S-licarbazepine R-licarbazepine 450 mg of S-licarbazepine plus 450 mg of R-licarbazepine
S-licarbazepine: capsules containing 225 mg
R-licarbazepine: capsules containing 225 mg | 8 |
| S-licarbazepine 450 mg of S-licarbazepine
S-licarbazepine: capsules containing 225 mg | 8 |
| R-licarbazepine 450 mg of Rlicarbazepine
R-licarbazepine: capsules containing 225 mg | 8 |
| Total | 32 |
Baseline characteristics
| Characteristic | Eslicarbazepine Acetate | S-licarbazepine R-licarbazepine | S-licarbazepine | R-licarbazepine | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 32 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 8 | 8 / 8 | 4 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity
BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine.
Time frame: Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eslicarbazepine Acetate | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-194) | 271191 ng.h/mL | Standard Deviation 47416 |
| Eslicarbazepine Acetate | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (Oxcarbazepine) | 3181 ng.h/mL | Standard Deviation 1078 |
| Eslicarbazepine Acetate | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-195) | 8816 ng.h/mL | Standard Deviation 2168 |
| S-licarbazepine R-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-194) | 201409 ng.h/mL | Standard Deviation 37377 |
| S-licarbazepine R-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (Oxcarbazepine) | 4726 ng.h/mL | Standard Deviation 1163 |
| S-licarbazepine R-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-195) | 116884 ng.h/mL | Standard Deviation 22425 |
| S-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-195) | 5417 ng.h/mL | Standard Deviation 824 |
| S-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-194) | 132724 ng.h/mL | Standard Deviation 20175 |
| S-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (Oxcarbazepine) | 2500 ng.h/mL | Standard Deviation 1923 |
| R-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-194) | 11003 ng.h/mL | Standard Deviation 4476 |
| R-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (Oxcarbazepine) | 1073 ng.h/mL | Standard Deviation 793 |
| R-licarbazepine | AUC0-∞ - the Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity | AUC0-∞ (BIA 2-195) | 66087 ng.h/mL | Standard Deviation 16072 |
Primary
Cmax - the Maximum Plasma Concentration
BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine.
Time frame: Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eslicarbazepine Acetate | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-194) | 15809 ng/mL | Standard Deviation 3183 |
| Eslicarbazepine Acetate | Cmax - the Maximum Plasma Concentration | Cmax (Oxcarbazepine) | 136 ng/mL | Standard Deviation 25.1 |
| Eslicarbazepine Acetate | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-195) | 222 ng/mL | Standard Deviation 68.4 |
| S-licarbazepine R-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-194) | 10496 ng/mL | Standard Deviation 1432 |
| S-licarbazepine R-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (Oxcarbazepine) | 261 ng/mL | Standard Deviation 53.5 |
| S-licarbazepine R-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-195) | 8099 ng/mL | Standard Deviation 1258 |
| S-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-195) | 132 ng/mL | Standard Deviation 29.6 |
| S-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-194) | 10364 ng/mL | Standard Deviation 3352 |
| S-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (Oxcarbazepine) | 92.8 ng/mL | Standard Deviation 21.8 |
| R-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-194) | 437 ng/mL | Standard Deviation 143 |
| R-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (Oxcarbazepine) | 101 ng/mL | Standard Deviation 28.6 |
| R-licarbazepine | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-195) | 6941 ng/mL | Standard Deviation 1054 |
Primary
Tmax - the Time of Occurrence of Cmax
BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine.
Time frame: Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eslicarbazepine Acetate | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-194) | 1.99 hours | Standard Deviation 0.916 |
| Eslicarbazepine Acetate | Tmax - the Time of Occurrence of Cmax | tmax (Oxcarbazepine) | 3.59 hours | Standard Deviation 1.61 |
| Eslicarbazepine Acetate | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-195) | 18.6 hours | Standard Deviation 4.14 |
| S-licarbazepine R-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-194) | 1.01 hours | Standard Deviation 0.32 |
| S-licarbazepine R-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (Oxcarbazepine) | 1.34 hours | Standard Deviation 0.354 |
| S-licarbazepine R-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-195) | 1.41 hours | Standard Deviation 0.32 |
| S-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-195) | 11.7 hours | Standard Deviation 3.77 |
| S-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-194) | 0.965 hours | Standard Deviation 0.496 |
| S-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (Oxcarbazepine) | 1.36 hours | Standard Deviation 1.44 |
| R-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-194) | 10.7 hours | Standard Deviation 3.69 |
| R-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (Oxcarbazepine) | 1.21 hours | Standard Deviation 0.641 |
| R-licarbazepine | Tmax - the Time of Occurrence of Cmax | tmax (BIA 2-195) | 1.22 hours | Standard Deviation 0.582 |
Secondary
AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point
BIA 2-194, BIA 2-195 and Oxcarbazepine are metabolites of BIA 2-093 and Licarbazepine.
Time frame: Phase A: pre-dose (Day 1); and ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.Phase B: Days 6 to 10 inclusively: pre-dose. Day 11 (last dose): pre-dose; and ½, 1, 1½,2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eslicarbazepine Acetate | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-194) | 268045 ng.h/mL | Standard Deviation 46861 |
| Eslicarbazepine Acetate | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (Oxcarbazepine) | 1947 ng.h/mL | Standard Deviation 757 |
| Eslicarbazepine Acetate | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-195) | 6757 ng.h/mL | Standard Deviation 2211 |
| S-licarbazepine R-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-194) | 198313 ng.h/mL | Standard Deviation 38771 |
| S-licarbazepine R-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (Oxcarbazepine) | 3401 ng.h/mL | Standard Deviation 902 |
| S-licarbazepine R-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-195) | 114635 ng.h/mL | Standard Deviation 21741 |
| S-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-195) | 3074 ng.h/mL | Standard Deviation 1001 |
| S-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-194) | 130147 ng.h/mL | Standard Deviation 19326 |
| S-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (Oxcarbazepine) | 748 ng.h/mL | Standard Deviation 308 |
| R-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-194) | 9419 ng.h/mL | Standard Deviation 4707 |
| R-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (Oxcarbazepine) | 422 ng.h/mL | Standard Deviation 247 |
| R-licarbazepine | AUC0-t - the Area Under the Plasma Concentration-time Curve to Last Measurable Time Point | AUC0-t (BIA 2-195) | 65203 ng.h/mL | Standard Deviation 16161 |