Efficacy and Safety of Eslicarbazepine Acetate (BIA 2-093) in Acute Manic Episodes Associated With Bipolar I Disorder

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.

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.

Eligibility Criteria:
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.