Bipolar I Disorder
Conditions
Brief summary
Multicentre, double-blind, randomised, parallel-group, placebo-controlled dose-titration study; depending on clinical efficacy, up-titration of dosage 3 and 6 days after start of treatment; maintenance of individual maximum dose for the rest of the total 3-week treatment period; subsequently, down-titration (according to the dose steps and the time intervals of up-titration) and administration of an established anti-manic therapy during the tapering-off period (in patients who discontinued treatment) or entry into a recurrence prevention study (Protocol PRA+SCO/BIA-2093-205; reported under separate cover) as an option for patients who responded to the study treatment
Detailed description
Objectives: The primary objective was to evaluate the dose-dependent efficacy of 2 dose-titration regimens of Eslicarbazepine Acetate (ESL) compared with placebo as therapy in patients with acute mania. The secondary objective was to evaluate the safety and tolerability of 2 dose-titration regimens of Eslicarbazepine Acetate in comparison to placebo.
Interventions
Eslicarbazepine Acetate, starting with 800 mg per day and up-titrated in 800 mg steps until 2400 mg (maximum dose) according to clinical response.
DRUGPlacebo
Placebo
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* aged ≥18 years; * 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) \[8\]; * currently displaying an acute manic (including mixed) episode according to the DSM-IV criteria; * a Young Mania Rating Scale (YMRS) total score of ≥20; * symptoms of the current manic episode starting within 2 weeks prior to randomisation (V2, Day 1); * able to undergo a standard evaluation, including clinical interview, ratings and laboratory studies; * signed informed consent form; * post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation; women of childbearing potential had to present a serum pregnancy test consistent with a non-gravid state and had to use double-barrier contraception until the post-study visit (PSV).
Exclusion criteria
* a history of schizophrenia or schizoaffective disorder, psychotic features or rapid cycling; * currently treated with carbamazepine or oxcarbazepine; * a 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 within the previous 3 months; * a 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 electrocardiogram (ECG) or laboratory abnormalities; * calculated creatinine clearance \<30 mL/min \[men: (140-age) x weight / serum creatinine x 72; women: (0.85) (140-age) x weight / serum creatinine x 72. Age in years, weight in kg, and serum creatinine in mg/dL\]; * pregnant or nursing; * participating in another drug clinical trial within the last 2 months before the randomisation 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; * a history or presence of bone marrow impairment or depression (introduced by protocol amendment No. 1); * a history or presence of acute intermittent porphyria (introduced by protocol amendment No. 1). Patients receiving treatment for bipolar disorder or other central nervous system disorders at randomisation were excluded from randomisation. If the patients had previously used such medications the following restrictions had to be taken into account: * Patients treated with bipolar disorder preventive medication (for carbamazepine or oxcarbazepine see
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Young Mania Rating Scale (YMRS) Total Score at the End of the 3-week Treatment Period, in Relation to the Baseline. | 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 centres: 23 centres: 2 centres in Austria, 6 centres in Czech Republic, 6 centres in Slovakia, 1 centre in Portugal, and 8 centres in Romania. First patient enrolled: 02 December 2005 Last patient completed: 23 November 2006
Pre-assignment details
Patients who met the selection criteria at the randomisation visit (visit 2, Day 1) were randomised to 1 of the 3 treatment groups
Participants by arm
| Arm | Count |
|---|---|
| BIA 2-093 - 2400 mg (Maximum Dose) Group 1: Eslicarbazepine Acetate, starting with 800 mg per day and up-titrated in 800 mg steps until 2400 mg (maximum dose) according to clinical response.
Eslicarbazepine Acetate : Eslicarbazepine Acetate, starting with 800 mg per day and up-titrated in 800 mg steps until 2400 mg (maximum dose) according to clinical response. | 57 |
| BIA 2-093 - 1800 mg (Maximum Dose) Group 2: Eslicarbazepine Acetate, starting with 600 mg per day and up-titrated in 600 mg steps until 1800 mg (maximum dose) according to clinical response.
Eslicarbazepine Acetate : Eslicarbazepine Acetate, starting with 600 mg per day and up-titrated in 600 mg steps until 1800 mg (maximum dose) according to clinical response. | 64 |
| Placebo Group 3: Placebo (change in daily number of tablets administered, according to clinical response).
Placebo : Placebo, sugar pill | 40 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 1 |
| Overall Study | Lack of Efficacy | 3 | 6 | 5 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 4 | 4 |
Baseline characteristics
| Characteristic | BIA 2-093 - 2400 mg (Maximum Dose) | BIA 2-093 - 1800 mg (Maximum Dose) | Placebo | Total |
|---|---|---|---|---|
| Age, Customized 18 - 20 Years | 2 participants 19.3 | 0 participants 14.3 | 0 participants 22.5 | 2 participants 12.98 |
| Age, Customized 20 - 30 Years | 9 participants 70.2 | 10 participants 76.2 | 9 participants 67.85 | 28 participants 12.79 |
| Age, Customized 30 - 40 Years | 15 participants 10.5 | 17 participants 9.5 | 8 participants 10 | 40 participants 13.19 |
| Age, Customized 40 - 50 Years | 15 participants | 16 participants | 11 participants | 42 participants |
| Age, Customized 50 - 60 Years | 10 participants | 15 participants | 8 participants | 33 participants |
| Age, Customized 60 - 70 Years | 6 participants | 5 participants | 3 participants | 14 participants |
| Age, Customized 70 - 80 Years | 0 participants | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 27 Participants | 36 Participants | 18 Participants | 81 Participants |
| Sex: Female, Male Male | 30 Participants | 28 Participants | 22 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 57 | 25 / 64 | 10 / 40 |
| serious Total, serious adverse events | 2 / 57 | 2 / 64 | 1 / 40 |
Outcome results
Primary
Change in the Young Mania Rating Scale (YMRS) Total Score at the End of the 3-week Treatment Period, in Relation to the Baseline.
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 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 (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIA 2-093 - 2400 mg (Maximum Dose) | Change in the Young Mania Rating Scale (YMRS) Total Score at the End of the 3-week Treatment Period, in Relation to the Baseline. | -14.2 units on a scale | Standard Error 1.17 |
| BIA 2-093 - 1800 mg (Maximum Dose) | Change in the Young Mania Rating Scale (YMRS) Total Score at the End of the 3-week Treatment Period, in Relation to the Baseline. | -12.5 units on a scale | Standard Error 1.12 |
| Placebo | Change in the Young Mania Rating Scale (YMRS) Total Score at the End of the 3-week Treatment Period, in Relation to the Baseline. | -10.3 units on a scale | Standard Error 1.4 |