Epilepsy
Conditions
Brief summary
Open-label, single-dose (BIA 2-093 800 mg tablet), single-centre study in five groups of subjects with various degrees of renal function based on creatinine clearance
Detailed description
This was an open-label, single-dose (BIA 2-093 800 mg tablet), single-centre study in five groups of subjects with various degrees of renal function based on creatinine clearance (stages of renal function according to the Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products Guidelines) for the evaluation of pharmacokinetics in patients with impaired renal function. The trial commenced with Groups 1 and 2. An interim safety evaluation was conducted and, as there were no safety concerns, the trial continued with Groups 3 and 4. After another interim safety evaluation with the data from Groups 3 and 4, the trial commenced with Group 5.
Interventions
DRUGBIA 2-093
Sponsors
Bial - Portela C S.A.
Study design
Allocation
NON_RANDOMIZED
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, with body mass not less than 50 kg. * Female subjects had to be post-menopausal, surgically sterilized or using a reliable method of contraception. * Subjects suffering from a chronic illness, other than hepatic impairment, had to have a stable condition, regarded by the investigator as unlikely to influence the outcome of the study. * Renal failure, the extent of which, as measured by the creatinine clearance, resulted in recruitment to one of five renal function groups. * Medical records indicating a stable serum creatinine (variation of not more than 30%), for at least 3 months prior to the screening visit (Groups 2 to 4 only), as determined by the clinical investigator. The sérum creatinine had to be stable to allow for an accurate determination of the creatinine clearance and therefore allowed for correct allocation to one of the renal function groups. Subjects who were recruited into Group 1 had normal renal function.
Exclusion criteria
* The receipt of any investigational drug within 30 days prior to this study. * Clinically significant abnormal findings (as judged by the investigator) for the following parameters, except those consistent with findings in renal failure: haematology, biochemistry, clotting profile, urinalysis, vital signs or ECG screening tests. * A history or laboratory evidence of hepatic impairment and/or disease. Owing to the metabolic pathway of BIA 2-093, any degree of hepatic impairment would have had a confounding effect on the PK analysis. * Positive test for 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 have been further worsened by the fact that the patients are invarious degrees of renal failure, 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 patients, which may be a part of the spectrum of complaints in HIV positive patients and Hepatitis B and C patients, would have confounded the safety and tolerability analysis. Furthermore, Hepatitis B and C, which may cause an element of hepatic impairment, would have confounded the PK analysis due to the metabolic pathway of BIA 2-093. In addition, by administering the study medication to these subjects, any adverse events that might have occurred would have added to the discomfort of the patient. * A history of any illness that, in the opinion of the Investigator and/or Sponsor, might have confounded the results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax - Peak Plasma Concentration | pre-dose and 1, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 7, 9, 12, 24, 48, 72 and 96 hours post-dose. | BIA 2-194; BIA 2-195; Oxcarbazepine are BIA 2-093 metabolites |
| AUC(0-12h) - AUC From Time Zero to 12h | pre-dose and 1, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 7, 9, 12, 24, 48, 72 and 96 hours post-dose. | BIA 2-194; BIA 2-195; Oxcarbazepine are BIA 2-093 metabolites AUC - area under the plasma concentration versus time curve |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax (hr) - Time at Which Cmax Occurred | pre-dose and 1, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 7, 9, 12, 24, 48, 72 and 96 hours post-dose. | BIA 2-194; BIA 2-195; Oxcarbazepine are BIA 2-093 metabolites Cmax - maximum observed plasma drug concentration |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Normal Renal Function normal renal function (creatinine clearance \> 80 mL/min)
BIA 2-093 | 8 |
| Group 2 Mild Renal Impairment mild renal impairment (creatinine clearance 50-80 mL/min)
BIA 2-093 | 8 |
| Group 3 Moderate Renal Impairment moderate renal impairment (creatinine clearance 30-50 mL/min)
BIA 2-093 | 8 |
| Group 4 Severe Renal Impairment severe renal impairment (creatinine clearance \<30 mL/min)
BIA 2-093 | 8 |
| Group 5 End Stage Renal Disease end stage renal disease, requiring haemodialysis (ESRD)
BIA 2-093 | 8 |
| Total | 40 |
Baseline characteristics
| Characteristic | Group 1 Normal Renal Function | Group 2 Mild Renal Impairment | Group 3 Moderate Renal Impairment | Group 4 Severe Renal Impairment | Group 5 End Stage Renal Disease | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 7 Participants | 7 Participants | 8 Participants | 8 Participants | 38 Participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 2 Participants | 1 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 7 Participants | 1 Participants | 6 Participants | 7 Participants | 5 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 8 | 6 / 8 | 5 / 8 | 4 / 8 | 3 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
AUC(0-12h) - AUC From Time Zero to 12h
BIA 2-194; BIA 2-195; Oxcarbazepine are BIA 2-093 metabolites AUC - area under the plasma concentration versus time curve
Time frame: pre-dose and 1, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 7, 9, 12, 24, 48, 72 and 96 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Normal Renal Function | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-195) | 1522.370 ng*h/mL | Standard Deviation 427.44 |
| Group 1 Normal Renal Function | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-194) | 105275.733 ng*h/mL | Standard Deviation 21516.315 |
| Group 1 Normal Renal Function | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (Oxcarbazepine) | 1218.276 ng*h/mL | Standard Deviation 279.55 |
| Group 2 Mild Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-194) | 150945.034 ng*h/mL | Standard Deviation 24049.32 |
| Group 2 Mild Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (Oxcarbazepine) | 1388.146 ng*h/mL | Standard Deviation 316.857 |
| Group 2 Mild Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-195) | 2435.245 ng*h/mL | Standard Deviation 681.175 |
| Group 3 Moderate Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-194) | 138473.115 ng*h/mL | Standard Deviation 19998.869 |
| Group 3 Moderate Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-195) | 2025.731 ng*h/mL | Standard Deviation 419.93 |
| Group 3 Moderate Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (Oxcarbazepine) | 1460.113 ng*h/mL | Standard Deviation 351.507 |
| Group 4 Severe Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (Oxcarbazepine) | 1496.463 ng*h/mL | Standard Deviation 653.928 |
| Group 4 Severe Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-194) | 138262.814 ng*h/mL | Standard Deviation 43286.475 |
| Group 4 Severe Renal Impairment | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-195) | 2157.860 ng*h/mL | Standard Deviation 1092.304 |
| Group 5 End Stage Renal Disease | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-195) | 2690.584 ng*h/mL | Standard Deviation 731.793 |
| Group 5 End Stage Renal Disease | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (BIA 2-194) | 134757.936 ng*h/mL | Standard Deviation 18609.384 |
| Group 5 End Stage Renal Disease | AUC(0-12h) - AUC From Time Zero to 12h | AUC(0-12h) (Oxcarbazepine) | 1832.298 ng*h/mL | Standard Deviation 338.896 |
Primary
Cmax - Peak Plasma Concentration
BIA 2-194; BIA 2-195; Oxcarbazepine are BIA 2-093 metabolites
Time frame: pre-dose and 1, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 7, 9, 12, 24, 48, 72 and 96 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Normal Renal Function | Cmax - Peak Plasma Concentration | Cmax (BIA 2-194) | 14286.790 ng/mL | Standard Deviation 2988.34 |
| Group 1 Normal Renal Function | Cmax - Peak Plasma Concentration | Cmax (Oxcarbazepine) | 138.339 ng/mL | Standard Deviation 32.271 |
| Group 1 Normal Renal Function | Cmax - Peak Plasma Concentration | Cmax (BIA 2-195) | 211.076 ng/mL | Standard Deviation 61.02 |
| Group 2 Mild Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (BIA 2-195) | 348.843 ng/mL | Standard Deviation 69.739 |
| Group 2 Mild Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (BIA 2-194) | 18677.265 ng/mL | Standard Deviation 4381.474 |
| Group 2 Mild Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (Oxcarbazepine) | 172.293 ng/mL | Standard Deviation 43.431 |
| Group 3 Moderate Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (BIA 2-195) | 410.828 ng/mL | Standard Deviation 68.663 |
| Group 3 Moderate Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (BIA 2-194) | 15055.632 ng/mL | Standard Deviation 2513.17 |
| Group 3 Moderate Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (Oxcarbazepine) | 157.629 ng/mL | Standard Deviation 35.224 |
| Group 4 Severe Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (BIA 2-194) | 14974.79 ng/mL | Standard Deviation 4313.9 |
| Group 4 Severe Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (Oxcarbazepine) | 157.955 ng/mL | Standard Deviation 61.354 |
| Group 4 Severe Renal Impairment | Cmax - Peak Plasma Concentration | Cmax (BIA 2-195) | 465.928 ng/mL | Standard Deviation 201.988 |
| Group 5 End Stage Renal Disease | Cmax - Peak Plasma Concentration | Cmax (BIA 2-195) | 359.798 ng/mL | Standard Deviation 119.819 |
| Group 5 End Stage Renal Disease | Cmax - Peak Plasma Concentration | Cmax (BIA 2-194) | 14510.197 ng/mL | Standard Deviation 2149.176 |
| Group 5 End Stage Renal Disease | Cmax - Peak Plasma Concentration | Cmax (Oxcarbazepine) | 208.473 ng/mL | Standard Deviation 40.912 |
Secondary
Tmax (hr) - Time at Which Cmax Occurred
BIA 2-194; BIA 2-195; Oxcarbazepine are BIA 2-093 metabolites Cmax - maximum observed plasma drug concentration
Time frame: pre-dose and 1, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 7, 9, 12, 24, 48, 72 and 96 hours post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Normal Renal Function | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-194) | 1.121 hours | Standard Deviation 0.53 |
| Group 1 Normal Renal Function | Tmax (hr) - Time at Which Cmax Occurred | Tmax (Oxcarbazepine) | 2.396 hours | Standard Deviation 0.773 |
| Group 1 Normal Renal Function | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-195) | 22.008 hours | Standard Deviation 4.243 |
| Group 2 Mild Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-195) | 20.185 hours | Standard Deviation 5.557 |
| Group 2 Mild Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-194) | 1.327 hours | Standard Deviation 1.004 |
| Group 2 Mild Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (Oxcarbazepine) | 2.581 hours | Standard Deviation 0.681 |
| Group 3 Moderate Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-195) | 26.172 hours | Standard Deviation 8.485 |
| Group 3 Moderate Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-194) | 2.609 hours | Standard Deviation 2.504 |
| Group 3 Moderate Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (Oxcarbazepine) | 3.970 hours | Standard Deviation 2.397 |
| Group 4 Severe Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-194) | 2.680 hours | Standard Deviation 2.642 |
| Group 4 Severe Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (Oxcarbazepine) | 4.787 hours | Standard Deviation 3.172 |
| Group 4 Severe Renal Impairment | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-195) | 33.947 hours | Standard Deviation 12.824 |
| Group 5 End Stage Renal Disease | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-195) | 10.773 hours | Standard Deviation 1.553 |
| Group 5 End Stage Renal Disease | Tmax (hr) - Time at Which Cmax Occurred | Tmax (BIA 2-194) | 1.633 hours | Standard Deviation 1.069 |
| Group 5 End Stage Renal Disease | Tmax (hr) - Time at Which Cmax Occurred | Tmax (Oxcarbazepine) | 4.260 hours | Standard Deviation 2.254 |