BIPOLAR I DISORDER
Conditions
Keywords
BIPOLAR I DISORDER, Eslicarbazepine acetate
Brief summary
The primary study objective was to evaluate the dose-dependent efficacy of eslicarbazepine acetate administered at doses of 600, 1200, and 1800 mg over a 3-week period, compared with placebo, as therapy in patients with acute mania. The secondary objectives of this study were to a) evaluate the safety and tolerability of eslicarbazepine acetate (BIA 2-093) administered at doses of 600, 1200, and 1800 mg compared with placebo, b) assess the duration to onset of action in the different dose groups, and c) monitor the appearance of depressive symptoms.
Detailed description
This was a phase II, double-blind, fixed multiple dose, randomised, placebo-controlled, multicentre clinical trial in patients with a diagnosis of bipolar I disorder who experienced an acute manic (including mixed) episode. Patients who met the selection criteria at randomisation visit (V) (V2, Day 1) were randomised to 1 of 4 treatment groups: 600, 1200, or 1800 mg eslicarbazepine acetate, or placebo. Patients started the assigned treatment on Day 1 and were followed for up to 3 weeks. On Day 10, patients who showed no improvement were switched to open-label escape therapy with an established antimanic therapy. Patients could have been hospitalized at screening or at any time during the study at the investigator's discretion. Following randomisation (V2, Day 1), patients were assessed on Days 3, 7, 10, 14, 21, 28, and 56, after which they could either enter a recurrence prevention study, or the study drug could be tapered off and they could undergo follow-up assessments.
Interventions
DRUGEslicarbazepine acetate 1800 mg
Eslicarbazepine acetate to be taken orally, was available as 600 mg tablets.
Eslicarbazepine acetate to be taken orally, was available as 600 mg tablets.
DRUGEslicarbazepine acetate 600 mg
Eslicarbazepine acetate to be taken orally, was available as 600 mg tablets.
DRUGPlacebo
Placebo sugar pills
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged 18 years or more. * A documented diagnosis of bipolar I disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria (i.e., 296.0, 296.4 or 296.6). * Currently displaying an acute manic (including mixed) episode according to the DSM-IV criteria. * A Young Mania Rating Scale (YMRS) total score of 20 or greater. * Symptoms of the current manic episode starting within 2 weeks prior to Randomization (V2, Day 1). * Able to undergo a standard evaluation, including clinical interview, ratings and laboratory studies. * Signed informed consent form (ICF). * Post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation. In case of woman of childbearing potential, patient presents a serum pregnancy test consistent with a non-gravid state and will use double-barrier contraception until at least the post-study visit (PSV).
Exclusion criteria
* History of schizophrenia or schizoaffective disorder, psychotic features or rapid cycling. * Currently treated with carbamazepine or oxcarbazepine. * History of unresponsiveness, intolerance or hypersensitivity to related compounds (carbamazepine, oxcarbazepine or licarbazepine). * Use of any depot-neuroleptics for the current manic episode * Abuse of stimulating drugs or use of any systemic sympathicomimetic drug within the previous 2 weeks. * Electroconvulsive therapy (ECT) within the previous 3 months * History of dependence or chronic abuse from alcohol, drugs or medications within the last year. * Judged clinically to be at risk of harm to self or others. * Second or third-degree atrioventricular blockade not corrected with a pacemaker. * Relevant ECG or laboratory abnormalities. * Calculated creatinine clearance \<30 ml/min \[men: (140-age) x weight / serum creatinine x 72; women: (0.85) (140-age) x weight / serum creatinine x 72. Age in years, weight in kg, and serum creatinine in mg/dl\]. * Pregnancy or nursing. * Participation in other drug clinical trial within the last 2 months before Randomization visit * Not ensured capability to perform the trial or to comply with the study protocol (e.g. mental retardation or severe inability to communicate); * Any other uncontrolled clinically relevant disorder. * Previous treatment with Eslicarbazepine Acetate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Young Mania Rating Scale (YMRS) Total Score From Baseline Until the End of the 3-week Treatment Period | baseline and 3-week | The YMRS is used to assess disease severity in patients who have been previously diagnosed with mania and it has proven psychometric properties through 11 item multiple-choice diagnostic questionnaire and the total score is determined from the summation of each 11 individual scores (and can range from 0 - 60) based on the patient's subjective feedback of his clinical condition over the previous 48 hours. A higher score indicates a worse rating for symptoms related to mania. At every visit throughout the study, investigators administered the YMRS. The results of the primary analysis of efficacy were calculated using Analysis of covariance (ANCOVA) with Last Observation Carried Forward (LOCF). Primary variable is presented through ANCOVA results for absolute change in YMRS total score from baseline (V2) to end of treatment (V7). A responder has at least 50% improvement (reduction) in the YMRS total score or has a total score of less than 12 points at the end of treatment period. |
Participant flow
Recruitment details
STUDY DATES: From: 28 Feb 2006 To: 13 Nov 2006 Study centers: 25 study centers in Europe, South Africa and South America: 7 centers in Croatia, 6 centers in Spain, 6 centers in Argentina, 1 center in Chile and 5 centers in South Africa.
Pre-assignment details
Patients who met the selection criteria at randomisation visit (V) (V2, Day 1) were randomised to 1 of 4 treatment groups: 600, 1200, or 1800 mg eslicarbazepine acetate, or placebo. Patients started the assigned treatment on Day 1 and were followed for up to 3 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Group 4: Placebo Placebo pills
Placebo : Placebo sugar pills | 11 |
| Group 3: Eslicarbazepine Acetate 600 mg Eslicarbazepine acetate 600 mg
Eslicarbazepine acetate 600 mg : Eslicarbazepine acetate to be taken orally, was available as 600 mg tablets. | 8 |
| Group 2: Eslicarbazepine Acetate 1200 mg Eslicarbazepine acetate 1200 mg
Eslicarbazepine acetate 1200 mg : Eslicarbazepine acetate to be taken orally, was available as 600 mg tablets. | 9 |
| Group 1: Eslicarbazepine Acetate 1800 mg Eslicarbazepine acetate 1800 mg
Eslicarbazepine acetate 1800 mg : Eslicarbazepine acetate to be taken orally, was available as 600 mg tablets. | 10 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 | 2 |
| Overall Study | Patient non-compliance | 0 | 0 | 1 | 0 |
| Overall Study | Treatment failure | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Group 4: Placebo | Group 3: Eslicarbazepine Acetate 600 mg | Group 2: Eslicarbazepine Acetate 1200 mg | Group 1: Eslicarbazepine Acetate 1800 mg | Total |
|---|---|---|---|---|---|
| Age, Customized <=18 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized >=65 years | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Age, Customized Between 18 and 65 years | 11 participants | 8 participants | 9 participants | 9 participants | 37 participants |
| Sex: Female, Male Female | 8 Participants | 1 Participants | 9 Participants | 4 Participants | 22 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 0 Participants | 6 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 | 7 / 11 | 4 / 8 | 9 / 9 | 10 / 10 |
| serious Total, serious adverse events | 1 / 11 | 0 / 8 | 0 / 9 | 1 / 10 |
Outcome results
Primary
Change in Young Mania Rating Scale (YMRS) Total Score From Baseline Until the End of the 3-week Treatment Period
The YMRS is used to assess disease severity in patients who have been previously diagnosed with mania and it has proven psychometric properties through 11 item multiple-choice diagnostic questionnaire and the total score is determined from the summation of each 11 individual scores (and can range from 0 - 60) based on the patient's subjective feedback of his clinical condition over the previous 48 hours. A higher score indicates a worse rating for symptoms related to mania. At every visit throughout the study, investigators administered the YMRS. The results of the primary analysis of efficacy were calculated using Analysis of covariance (ANCOVA) with Last Observation Carried Forward (LOCF). Primary variable is presented through ANCOVA results for absolute change in YMRS total score from baseline (V2) to end of treatment (V7). A responder has at least 50% improvement (reduction) in the YMRS total score or has a total score of less than 12 points at the end of treatment period.
Time frame: baseline and 3-week
Population: The ITT efficacy population of 37 patients consisted of all randomised patients who received at least one dose of investigational product and at least 1 post-baseline YMRS assessment. If a patient discontinues before the end of the 3-week treatment period then the last observation will be carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Young Mania Rating Scale (YMRS) Total Score From Baseline Until the End of the 3-week Treatment Period | -17.7 units on a scale | Standard Error 7.34 |
| ESL 600 mg | Change in Young Mania Rating Scale (YMRS) Total Score From Baseline Until the End of the 3-week Treatment Period | -16.9 units on a scale | Standard Error 2.75 |
| ESL 1200 mg | Change in Young Mania Rating Scale (YMRS) Total Score From Baseline Until the End of the 3-week Treatment Period | -16.7 units on a scale | Standard Error 9.11 |
| ESL 1800 mg | Change in Young Mania Rating Scale (YMRS) Total Score From Baseline Until the End of the 3-week Treatment Period | -11.3 units on a scale | Standard Error 10.89 |