A Phase IV Study of the Safety and Efficacy of Aripiprazole in Combination With Lamotrigine in the Long-Term Maintenance Treatment of Patients With Bipolar I Disorder With A Recent Manic or Mixed Episode

Study Overview
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Brief Summary
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Efficacy of Aripiprazole in Combination with Lamotrigine in the Long-Term Maintenance Treatment of Bipolar I Disorder in Outpatients with Recent Manic or Mixed Episode

Official Title
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A Multicenter, Double-blind, Study of the Efficacy and Safety of Aripiprazole in Combination With Lamotrigine in the Long-term Maintenance Treatment of Patients With Bipolar I Disorder With a Recent Manic or Mixed Episode

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Lamotrigine + Aripiprazole
* Drug: Lamotrigine + Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years of age meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision) (DSM-IV-TR) criteria for bipolar I disorder, recently experiencing a manic or mixed episode with a history of one or more manic or mixed episodes of sufficient severity to require treatment with a mood stabilizer or antipsychotic Exclusion Criteria: First manic episode Current manic or mixed episode with > 2 years duration Treated with aripiprazole within the past 3 months Allergic, intolerant, hypersensitive or refractory to aripiprazole or lamotrigine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1<br>Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole ; Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole | Drug: Lamotrigine + Aripiprazole<br>* Tablets, Oral, once daily, Phase 1 (all subjects) - up to 24 weeks; Phase 2 - up to 52 weeks Lamotrigine 100-200 mg/day Aripiprazole 10-30 mg/day<br>* Other names: BMS-337039;|
| Placebo Comparator: A2<br>Phase 2 Double-Blind Treatment: Lamotrigine + Placebo | Drug: Lamotrigine + Placebo<br>* Tablets, Oral, once daily, Phase 2 - up to 52 weeks Lamotrigine 100-200 mg/day placebo 0 mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Not Experiencing Relapse Through Week 52 in the Double-Blind Relapse Assessment Phase (Phase 2) | Time from randomization to relapse to a manic or mixed episode in the Double-Blind Relapse Assessment Phase as measured by the Proportion of Participants without Relapse Through Week 52 (Kaplan-Meier's estimated survival rate). | Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Not Experiencing Relapse (Manic, Mixed, Depressive) in the Double-blind Relapse Assessment Phase Phase 2 | Proportion of Participants without Relapse Through Week 52 (Kaplan-Meier's estimated survival rate). | Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 
| Proportion of Participants Not Experiencing a Depressive Relapse in the Double-blind Relapse Assessment Phase (Phase 2) | Proportion of Participants without Relapse Through Week 52 (Kaplan-Meier's estimated survival rate). | Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 
| Proportion of Participants Without Discontinuation for Any Reason in the Double-blind Relapse Assessment Phase (Phase 2) | Proportion of Participants without Discontinuation Through Week 52(Kaplan-Meier's estimated survival rate). | Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 
| Deaths, Treatment-Emergent Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation of Study Medication, Treatment-Emergent AEs and Treatment-Emergent Extrapyramidal Syndrome (EPS)-Related AEs | AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event. | Throughout Phase 2 (up to 52 weeks) | 
| Adjusted Mean Change From Baseline in Body Weight, Phase 2 | Adjusted for index mood episode and baseline assessment | Baseline, Week 52 | 
| Number of Participants Showing Clinically Relevant Weight Loss by Study Week | Weight Loss of at least a 7% decrease from Baseline. | Weeks 12, 24, 36, 52 | 
| Number of Participants Showing Clinically Relevant Weight Gain by Study Week | Weight gain of at least a 7% increase from Baseline. | Weeks 12, 24, 36, 52 | 
| Adjusted Mean Change From Baseline in BMI by Study Week | Adjusted for index mood episode and baseline assessment. | Baseline, Weeks 12, 24, 36, 52 | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities Occurring During Double-Blind Treatment | Abbreviations and further description used in table: Sinus tachycardia, ≥120 beats per minute (bpm) and ↑ ≥15 bpm & no current diagnosis of supraventricular or ventricular tachycardia/atrial fibrillation (AF)/atrial flutter/ other rhythm abnormality. Sinus bradycardia, ≤ 50 bpm and ↓ 15 bpm & no current diagnosis of AF/atrial flutter/other rhythm abnormality. Supraventricular premature beat (SPB), Ventricular premature beat (VPB), Atroventricular (A-V). Other intraventricular block, QRS ≥0.12 sec and ↑ ≥0.02 sec & no current diagnosis of left or right bundle branch block. | Throughout the study, up to Week 52 | 
| Number of Participants With Potentially Clinically Relevant Vital Sign Abnormalities Occurring During Double-Blind Treatment | In order to be identified as clinically relevant abnormal, an on-drug value must meet the Criterion Value (CV) and also represent a change from the patient's pretreatment value of at least the Change Relative to Baseline (CRB) magnitude. Heart Rate CV: 120 beats per minute (bpm), CRB: increase of ≥15 / CV: 50 bpm, CRB: decrease of ≥15. Systolic BP CV: 180 mmHg, CRB: increase of ≥20 / CV: 90 mmHg, CRB: decrease of ≥20. Diastolic BP CV: 105 mmHg, CRB: increase of ≥15 / CV: 50 mmHg, CRB: decrease of ≥15. | Up to 52 Weeks | 
| Number of Participants With Potentially Clinically Relevant Laboratory Abnormalities Occurring During Double-Blind Treatment (Phase 2) | Chemistry, hematology, and urinalysis abnormalities.Abbreviations used: alanine aminotransferase (ALT), institutional upper limit of normal (ULN), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), baseline (BL) | Throughout Phase 2 of the study, up to Week 52 | 
| Summary of Concomitant Medications, Phase 1 |  | Phase 1 (9 to 24 Week Single-blind Stabilization Phase) | 
| Summary of Concomitant Medications, Phase 2 |  | Phase 2 (52 Week Double-blind Relapse Assessment Phase) | 
| Adjusted Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score | The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50. Negative change scores indicate improvement. | Baseline, Weeks 8, 24, 36, 52 | 
| Adjusted Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score | The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction. | Baseline, Weeks 8, 24, 36, 52 | 
| Adjusted Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment, | The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia. | Baseline, Weeks 8, 24, 36, 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar I Disorder with a recent manic or mixed episode