Epilepsy
Conditions
Brief summary
Open-label, multiple-dose, single-centre study in 2 groups of subjects: subjects with moderate hepatic impairment and healthy controls. The trial consisted of a screening visit, a treatment phase and a follow-up visit. All subjects were to be treated with study medication for 8 consecutive days. Blood and urine were collected for the PK analysis, and safety assessments were performed.
Detailed description
The screening visit was performed 2 to 21 days before the first administration of study medication, the treatment phase consisted of 12 days (of which study medication was administered during the first 8 days), and the follow-up visit was performed 15 to 19 days after the first administration of study medication.
Interventions
DRUGBIA 2-093
Sponsors
Bial - Portela C S.A.
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Males and females at least 18 years of age. * Female subjects had to be post-menopausal, surgically sterilized or using a reliable non-hormonal method of contraception. Examples of reliable non-hormonal methods of contraception include tubal ligation, hysterectomy, intrauterine device, or a barrier method combined with a spermicide. Hormonal contraceptives were not allowed because the effect of BIA 2-093 on the metabolism of oral contraceptives was not yet known. * Subjects suffering from a chronic illness, other than hepatic impairment, had to have a stable condition, regarded by the investigator as not able to influence the outcome of the study. * For subjects to be included in Group 1, a stage of moderate hepatic impairment, the extent of which, as measured by the Child-Pugh classification, resulted in recruitment into the study (Group 1 only). This did not apply to subjects that were recruited into Group 2, whose liver functioning was to be normal. * Body mass not less than 50 kg.
Exclusion criteria
* The receipt of any investigational drug within the 30 days prior to this trial. * Clinically significant abnormal findings (as judged by the investigator) for the following parameters, except those consistent with findings in hepatic impairment: haematology, biochemistry, clotting profile, urinalysis, vital signs or ECG screening tests. * A history or laboratory evidence of renal impairment and/or disease. Owing to the metabolic pathway of BIA 2-093, any degree of renal impairment would have had a confounding effect on the PK analysis. * Positive test for Human Immunodeficiency Virus (HIV)-1 or HIV-2 antibodies, Hepatitis B surface antigen and Hepatitis C antibodies. HIV positive patients, and patients with Hepatitis B and C, generally have a below average, and in some cases a markedly decreased, level of health owing to the nature of the respective infections and the natural course of the diseases, both of which are often complicated by an array of opportunistic illnesses. Their ill health would be further worsened by the fact that the patients are hepatically impaired, which has its own, often debilitating, complications. If patients with HIV or Hepatitis B or C were included in the study, this could have led to statistical confusion when assessing the safety and tolerability parameters. This is because events reported by the subjects, which might be a part of the spectrum of complaints in HIV positive patients and Hepatitis B and C patients, would confound the safety and tolerability analysis. In addition, by administering the study medication to these patients, any AEs that might have occurred would add to the discomfort of the patient. * A history of any illness that, in the opinion of the investigator and/or sponsor, might confound the results of the study or pose additional risk in administering the investigational product to the subject. * Any planned procedures and/or devices to be performed/added during the course of the study, which might influence the evaluation of the endpoints of the study. * Current addiction to alcohol as determined by the investigator. * Use of any medication, prescribed or over-the-counter, except drugs indicated for the treatment of concomitant illnesses in subjects with moderate hepatic impairment, or if the drugs would not have affected the outcome of the study in the opinion of the investigator. Vitamin use was allowed, but should have been stable during the course of the study. * Current treatment with oxcarbazepine. * Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation. * Subjects with a supine pulse rate at screening, after resting for 5 min, outside the range of 50 - 100 beats per minute (bpm). * A history of multiple and/or severe allergies to drugs or foods or a history of anaphylactic reactions. * Known or suspected allergy to trial product or related products (e.g carbamazepine or oxcarbazepine). * Female subjects who were pregnant or lactating. * Previous participation in (recruitment into) this trial. * Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before dose administration. * Any history of a bleeding tendency, or an active bleed in the preceding 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | pre-dose and 1, 2, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 7, 9, 12 and 24 hours post-dose. | Day 1 - Area under the plasma concentration versus time curve, AUC(0-tlast). BIA 2-194, 2-195 Glucoronide, Oxcarbazepine, BIA 2-093 Glucoronide, 2-194 Glucoronide are BIA 2-093 metabolites. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax - Peak Plasma Concentration | pre-dose and 1, 2, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 7, 9, 12 and 24 hours post-dose. | Day 1 - Cmax Peak plasma concentration |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Subjects With Moderate Hepatic Impairment This was an open-label, multiple-dose, single-centre study in 2 groups of subjects: subjects with moderate hepatic impairment and healthy controls
BIA 2-093 | 9 |
| Subjects - Healthy Controls This was an open-label, multiple-dose, single-centre study in 2 groups of subjects: subjects with moderate hepatic impairment and healthy controls
BIA 2-093 | 8 |
| Total | 17 |
Baseline characteristics
| Characteristic | Subjects With Moderate Hepatic Impairment | Subjects - Healthy Controls | 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 | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 9 | 4 / 8 |
| serious Total, serious adverse events | 1 / 9 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast).
Day 1 - Area under the plasma concentration versus time curve, AUC(0-tlast). BIA 2-194, 2-195 Glucoronide, Oxcarbazepine, BIA 2-093 Glucoronide, 2-194 Glucoronide are BIA 2-093 metabolites.
Time frame: pre-dose and 1, 2, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 7, 9, 12 and 24 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Subjects With Moderate Hepatic Impairment | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-093 | 954.891 h·ng/mL | Standard Deviation 963.751 |
| Subjects With Moderate Hepatic Impairment | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-194 | 240188.369 h·ng/mL | Standard Deviation 27773.762 |
| Subjects With Moderate Hepatic Impairment | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) 2-195 Glucoronide | 50.603 h·ng/mL | Standard Deviation 44.226 |
| Subjects With Moderate Hepatic Impairment | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) Oxcarbazepine | 1489.530 h·ng/mL | Standard Deviation 1055.93 |
| Subjects With Moderate Hepatic Impairment | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-093 Glucoronide | 6.875 h·ng/mL | Standard Deviation 2.312 |
| Subjects With Moderate Hepatic Impairment | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-194 Glucoronide | 8634.780 h·ng/mL | Standard Deviation 5915.045 |
| Subjects - Healthy Controls | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-093 Glucoronide | 2.500 h·ng/mL | Standard Deviation 2.5 |
| Subjects - Healthy Controls | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-093 | 49.750 h·ng/mL | Standard Deviation 27.931 |
| Subjects - Healthy Controls | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) Oxcarbazepine | 1899.092 h·ng/mL | Standard Deviation 915.761 |
| Subjects - Healthy Controls | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-194 | 234750.429 h·ng/mL | Standard Deviation 31036.558 |
| Subjects - Healthy Controls | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) BIA 2-194 Glucoronide | 11642.372 h·ng/mL | Standard Deviation 11102.059 |
| Subjects - Healthy Controls | Area Under the Plasma Concentration Versus Time Curve, AUC(0-tlast). | AUC(0-tlast) 2-195 Glucoronide | 157.738 h·ng/mL | Standard Deviation 199.859 |
Secondary
Cmax - Peak Plasma Concentration
Day 1 - Cmax Peak plasma concentration
Time frame: pre-dose and 1, 2, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 7, 9, 12 and 24 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Subjects With Moderate Hepatic Impairment | Cmax - Peak Plasma Concentration | Cmax 2-195 Glucoronide | 16.875 ng/mL | Standard Deviation 19.045 |
| Subjects With Moderate Hepatic Impairment | Cmax - Peak Plasma Concentration | Cmax Oxcarbazepine | 100.111 ng/mL | Standard Deviation 51.948 |
| Subjects With Moderate Hepatic Impairment | Cmax - Peak Plasma Concentration | Cmax BIA 2-093 Glucoronide | 9.000 ng/mL | Standard Deviation 2.449 |
| Subjects With Moderate Hepatic Impairment | Cmax - Peak Plasma Concentration | Cmax BIA 2-194 | 16392.778 ng/mL | Standard Deviation 3508.757 |
| Subjects With Moderate Hepatic Impairment | Cmax - Peak Plasma Concentration | Cmax BIA 2-194 Glucoronide | 1067.000 ng/mL | Standard Deviation 517.493 |
| Subjects With Moderate Hepatic Impairment | Cmax - Peak Plasma Concentration | Cmax BIA 2-093 | 477.500 ng/mL | Standard Deviation 439.131 |
| Subjects - Healthy Controls | Cmax - Peak Plasma Concentration | Cmax BIA 2-194 Glucoronide | 1381.125 ng/mL | Standard Deviation 973.778 |
| Subjects - Healthy Controls | Cmax - Peak Plasma Concentration | Cmax BIA 2-093 | 99.500 ng/mL | Standard Deviation 55.861 |
| Subjects - Healthy Controls | Cmax - Peak Plasma Concentration | Cmax BIA 2-194 | 18180.000 ng/mL | Standard Deviation 1996.97 |
| Subjects - Healthy Controls | Cmax - Peak Plasma Concentration | Cmax Oxcarbazepine | 121.000 ng/mL | Standard Deviation 63.042 |
| Subjects - Healthy Controls | Cmax - Peak Plasma Concentration | Cmax BIA 2-093 Glucoronide | 5.000 ng/mL | Standard Deviation 5 |
| Subjects - Healthy Controls | Cmax - Peak Plasma Concentration | Cmax 2-195 Glucoronide | 16.667 ng/mL | Standard Deviation 15.539 |