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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00277212
• Collaborator: Otsuka America Pharmaceutical (Industry)
• Enrollment: 1,169
• Locations: 66
• Arms: 2
• Duration (Months): 43
• Patients Per Site: 17.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Lamotrigine + Aripiprazole; Drug: Lamotrigine + Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 1169 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A1 Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole ; Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole	Drug: Lamotrigine + Aripiprazole; 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; Other Names: Abilify BMS-337039
Placebo Comparator: A2 Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Drug: Lamotrigine + Placebo; Tablets, Oral, once daily, Phase 2 - up to 52 weeks Lamotrigine 100-200 mg/day placebo 0 mg/day

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants Not Experiencing Relapse Through Week 52 in the Double-Blind Relapse Assessment Phase (Phase 2) [Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52]

   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).

Secondary Outcome Measures

1. Proportion of Participants Not Experiencing Relapse (Manic, Mixed, Depressive) in the Double-blind Relapse Assessment Phase Phase 2 [Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52]

   Proportion of Participants without Relapse Through Week 52 (Kaplan-Meier's estimated survival rate).

2. Proportion of Participants Not Experiencing a Depressive Relapse in the Double-blind Relapse Assessment Phase (Phase 2) [Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52]

   Proportion of Participants without Relapse Through Week 52 (Kaplan-Meier's estimated survival rate).

3. Proportion of Participants Without Discontinuation for Any Reason in the Double-blind Relapse Assessment Phase (Phase 2) [Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52]

   Proportion of Participants without Discontinuation Through Week 52(Kaplan-Meier's estimated survival rate).

4. 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 [Throughout Phase 2 (up to 52 weeks)]

   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.

5. Adjusted Mean Change From Baseline in Body Weight, Phase 2 [Baseline, Week 52]

   Adjusted for index mood episode and baseline assessment

6. Number of Participants Showing Clinically Relevant Weight Loss by Study Week [Weeks 12, 24, 36, 52]

   Weight Loss of at least a 7% decrease from Baseline.

7. Number of Participants Showing Clinically Relevant Weight Gain by Study Week [Weeks 12, 24, 36, 52]

   Weight gain of at least a 7% increase from Baseline.

8. Adjusted Mean Change From Baseline in BMI by Study Week [Baseline, Weeks 12, 24, 36, 52]

   Adjusted for index mood episode and baseline assessment.

9. Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities Occurring During Double-Blind Treatment [Throughout the study, up to Week 52]

   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.

10. Number of Participants With Potentially Clinically Relevant Vital Sign Abnormalities Occurring During Double-Blind Treatment [Up to 52 Weeks]

    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.

11. Number of Participants With Potentially Clinically Relevant Laboratory Abnormalities Occurring During Double-Blind Treatment (Phase 2) [Throughout Phase 2 of the study, up to Week 52]

    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)

12. Summary of Concomitant Medications, Phase 1 [Phase 1 (9 to 24 Week Single-blind Stabilization Phase)]

13. Summary of Concomitant Medications, Phase 2 [Phase 2 (52 Week Double-blind Relapse Assessment Phase)]

14. Adjusted Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score [Baseline, Weeks 8, 24, 36, 52]

    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.

15. Adjusted Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score [Baseline, Weeks 8, 24, 36, 52]

    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.

16. Adjusted Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment, [Baseline, Weeks 8, 24, 36, 52]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Of Alabama At Birmingham	Birmingham	Alabama	United States	35205
2	Southwest Biomedical Research Foundation	Tucson	Arizona	United States	85712
3	Pravin Kansagra, M.D.	Anaheim	California	United States	92801
4	College Hospital Costa Mesa	Costa Mesa	California	United States	92627
5	Pacific Institute For Medical Research, Inc.	Los Angeles	California	United States	90024
6	Excell Research	Oceanside	California	United States	92056
7	Southern Ca Clinical Research, Inc.	Pasadena	California	United States	91106
8	Stanford University	Stanford	California	United States	94305
9	Los Angeles Biomedical Research Institute	Torrance	California	United States	90502
10	Pacific Clinical Research Medical Group	Upland	California	United States	91786
11	Health Sciences America, Llc	Boca Raton	Florida	United States	33432
12	Cns Clinical Research Group	Coral Springs	Florida	United States	33065
13	Act Clinical Research Institute, Llc	Daytona Beach	Florida	United States	32124
14	Neuropsychiatric Research Center Of Southwest Florida	Fort Myers	Florida	United States	33912
15	Aurora-Cuervo Clinical Trials	Miami	Florida	United States	33143
16	Gulf Coast Medical Research	Port Charlotte	Florida	United States	33952
17	Janus Center For Psychiatric Research	West Palm Beach	Florida	United States	33407
18	Comprehensive Neuroscience, Inc	Atlanta	Georgia	United States	30328
19	Valle Vista Health System	Greenwood	Indiana	United States	46143
20	Clinco	Terre Haute	Indiana	United States	47802
21	Clinical Trials Technology, Inc	Prairie Village	Kansas	United States	66206
22	Clinical Research Institute	Wichita	Kansas	United States	67213
23	University Of Kentucky, Dept. Of Psychiatry	Lexington	Kentucky	United States	40509
24	Owensboro Behavioral Care	Owensboro	Kentucky	United States	42301
25	Sheppard Pratt Health System	Baltimore	Maryland	United States	21285
26	Clinical Insights	Glen Burnie	Maryland	United States	21061
27	Capital Clinical Research Associates	Rockville	Maryland	United States	20852
28	Psychopharmacology Research Corporation	Farmington Hills	Michigan	United States	48334
29	University Of Minnesota	Minneapolis	Minnesota	United States	55455
30	Regions Hospital	St. Paul	Minnesota	United States	55101
31	Precise Research Centers	Flowood	Mississippi	United States	39232
32	University Of Medicine & Dentistry Of New Jersey	Cherry Hill	New Jersey	United States	08002
33	Buffalo Psychiatric Center	Buffalo	New York	United States	14213
34	Finger Lakes Clinical Research	Rochester	New York	United States	14618
35	Richmond Behavioral Associates	Staten Island	New York	United States	10312
36	Duke University Medical Center	Durham	North Carolina	United States	27705
37	Zarzar Psychiatric Associates, Pllc	Raleigh	North Carolina	United States	27607
38	Horizon Medical Services	Bismarck	North Dakota	United States	58501
39	Neuro Behavioral Clinical Research, Inc.	Canton	Ohio	United States	44708
40	Community Research	Cincinnati	Ohio	United States	45227
41	Saroj Brar Md, Inc	Cleveland	Ohio	United States	44113
42	University Of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
43	Cutting Edge Research	Oklahoma City	Oklahoma	United States	73116
44	Summit Research Network	Portland	Oregon	United States	97210
45	Lehigh Valley Hospital	Allentown	Pennsylvania	United States	18103
46	Lehigh Center For Clinical Research	Allentown	Pennsylvania	United States	18104
47	Dubois Regional Medical Center	Dubois	Pennsylvania	United States	15801
48	Freimer, Martin	East Stroudsburg	Pennsylvania	United States	18301
49	University Of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
50	Belmont Center For Comprehensive Treatment	Philadelphia	Pennsylvania	United States	19131
51	Cns Research Institute	Philadelphia	Pennsylvania	United States	19149
52	Ut Medical Group/Odyssey Research	Memphis	Tennessee	United States	38105
53	Psychiatric Consultants, Pc	Nashville	Tennessee	United States	37203
54	Harmony Research, Llc	Piney Flats	Tennessee	United States	37686
55	Bayou City Research, Ltd.	Houston	Texas	United States	77007
56	Alamo Superior Research	San Antonio	Texas	United States	78229
57	University Of Virginia Health System	Charlottesville	Virginia	United States	22903
58	Windwood Centre	Virginia Beach	Virginia	United States	23452
59	Pacific Institute Of Medical Sciences	Bothell	Washington	United States	98011
60	Summit Research Network (Seattle) Llc	Seattle	Washington	United States	98104
61	Health Research Center	Morgantown	West Virginia	United States	26506
62	Aurora Health Care	Milwaukee	Wisconsin	United States	53233
63	Local Institution	Cabo Rojo		Puerto Rico	00623
64	Local Institution	Ponce		Puerto Rico	00731
65	Local Institution	Rio Piedras		Puerto Rico	00926
66	Local Institution	San Juan		Puerto Rico	00918

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.
• Otsuka America Pharmaceutical

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00277212
• Other Study ID Numbers: CN138-392 ST
• First Posted: Jan 16, 2006
• Last Update Posted: Dec 2, 2013
• Last Verified: Nov 1, 2010

• Keywords provided by , ,: Bipolar I Disorder with a recent manic or mixed episode
• Additional relevant MeSH terms: Disease; Bipolar Disorder; Lamotrigine; Anticonvulsants; Aripiprazole

Study Results

Participant Flow

Pre-assignment Detail	A total of 1169 patients were enrolled in the study; 382 participants were considered baseline failures and did not enter Phase 1.

Arm/Group Title	Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 1 (all subjects) - up to 24 weeks	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Period Title: Phase 1 - Single-Blind Treatment
STARTED	787	0	0
Phase 1 Safety Sample	787	0	0
Phase 1 Efficacy Sample	756	0	0
COMPLETED	352	0	0
NOT COMPLETED	435	0	0
Period Title: Phase 1 - Single-Blind Treatment
STARTED	0	173	178
Phase 2 Safety Sample	0	165	176
Phase 2 Efficacy Sample	0	164	174
COMPLETED	0	53	65
NOT COMPLETED	0	120	113

Baseline Characteristics

Arm/Group Title	Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 1 (all subjects) - up to 24 weeks
Overall Participants	796
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.1 (12.0)
Sex: Female, Male (Count of Participants)
Female	505 63.4%
Male	291 36.6%
Race/Ethnicity, Customized (participants) [Number]
White	693 87.1%
Black/African American	88 11.1%
Asian	10 1.3%
American Indian/Alaska Native	2 0.3%
Native Hawaiian/Other Pacific Islander	1 0.1%
Other	2 0.3%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	93 11.7%
Not Hispanic or Latino	703 88.3%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.7 (7.6)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	84.7 (22.7)
BMI Category (participants) [Number]
18.5 <= BMI <25	221 27.8%
25 <= BMI <30	215 27%
BMI <18.5	12 1.5%
BMI >=30	321 40.3%
Missing	27 3.4%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants Not Experiencing Relapse Through Week 52 in the Double-Blind Relapse Assessment Phase (Phase 2)
Description	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).
Time Frame	Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52

Outcome Measure Data

Analysis Population Description

Randomized Participants (comprises all patients who are randomized in Phase 2). n= number of randomized participants evaluated at given time point.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	173	178
Week 0 (n=173, n=178)	1.00 0.1%	1.00 NaN
Week 2 (n=162, n=172)	0.98 0.1%	0.98 NaN
Week 4 (n=154, n=159)	0.97 0.1%	0.96 NaN
Week 6 (n=142, n=147)	0.95 0.1%	0.93 NaN
Week 8 (n=135, n=135)	0.93 0.1%	0.90 NaN
Week 12 (n=121, n=127)	0.89 0.1%	0.90 NaN
Week 16 (n=101, n=127)	0.88 0.1%	0.90 NaN
Week 20 (n=94, n=127)	0.88 0.1%	0.90 NaN
Week 24 (n=86, n=127)	0.84 0.1%	0.90 NaN
Week 28 (n=79, n=127)	0.81 0.1%	0.90 NaN
Week 32 (n=69, n=83)	0.78 0.1%	0.89 NaN
Week 36 (n=67, n=83)	0.78 0.1%	0.89 NaN
Week 40 (n=62, n=83)	0.77 0.1%	0.89 NaN
Week 44 (n=62, n=83)	0.77 0.1%	0.89 NaN
Week 48 (n=62, n=83)	0.77 0.1%	0.89 NaN
Week 52 (n=62, n=83)	0.77 0.1%	0.89 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	stratified Log-Rank test, controlling for type of index mood episode
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.552
	Confidence Interval	(2-Sided) 95%; 0.296 to 1.030
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox's proportional hazards model, with type of index modd episode as stratification factor, and randomized treatment group as covariate.

2. Secondary Outcome

Title	Proportion of Participants Not Experiencing Relapse (Manic, Mixed, Depressive) in the Double-blind Relapse Assessment Phase Phase 2
Description	Proportion of Participants without Relapse Through Week 52 (Kaplan-Meier's estimated survival rate).
Time Frame	Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52

Outcome Measure Data

Analysis Population Description

Randomized Participants (comprises all patients who are randomized in Phase 2). n= number of randomized participants evaluated at given time point.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	173	178
Week 0 (n=173, n=178)	1.00 0.1%	1.00 NaN
Week 2 (n=163, n=175)	0.96 0.1%	0.95 NaN
Week 4 (n=154, n=160)	0.91 0.1%	0.91 NaN
Week 6 (n=145, n=149)	0.87 0.1%	0.88 NaN
Week 8 (n=135, n=136)	0.83 0.1%	0.84 NaN
Week 12 (n=121, n=123)	0.76 0.1%	0.82 NaN
Week 16 (n=102, n=113)	0.75 0.1%	0.80 NaN
Week 20 (n=94, n=111)	0.74 0.1%	0.80 NaN
Week 24 (n=91, n=95)	0.69 0.1%	0.78 NaN
Week 28 (n=78, n=85)	0.65 0.1%	0.77 NaN
Week 32 (n=69, n=83)	0.62 0.1%	0.75 NaN
Week 36 (n=67, n=76)	0.62 0.1%	0.74 NaN
Week 40 (n=62, n=70)	0.61 0.1%	0.73 NaN
Week 44 (n=62, n=70)	0.61 0.1%	0.73 NaN
Week 48 (n=62, n=70)	0.61 0.1%	0.73 NaN
Week 52 (n=19, n=70)	0.58 0.1%	0.73 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments	p-value for equality of survival curves
	Method	Log Rank
	Comments	stratified log-rank test, controlling for type of index mood episode
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.671
	Confidence Interval	(2-Sided) 95%; 0.446 to 1.011
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole/placebo; Cox's proportional hazards model, with type of index mood episode as stratification facto, and randomized treatment group as covariate.

3. Secondary Outcome

Title	Proportion of Participants Not Experiencing a Depressive Relapse in the Double-blind Relapse Assessment Phase (Phase 2)
Description	Proportion of Participants without Relapse Through Week 52 (Kaplan-Meier's estimated survival rate).
Time Frame	Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52

Outcome Measure Data

Analysis Population Description

Randomized Participants (comprises all patients who are randomized in Phase 2). n= number of randomized participants evaluated at given time point.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	173	178
Week 0 (n=173, n=178)	1.00 0.1%	1.00 NaN
Week 2 (n=163, n=175)	0.98 0.1%	0.98 NaN
Week 4 (n=151, n=160)	0.94 0.1%	0.95 NaN
Week 6 (n=145, n=149)	0.91 0.1%	0.94 NaN
Week 8 (n=132, n=136)	0.89 0.1%	0.93 NaN
Week 12 (n=119, n=123)	0.85 0.1%	0.90 NaN
Week 16 (n=102, n=113)	0.84 0.1%	0.89 NaN
Week 20 (n=102, n=111)	0.84 0.1%	0.89 NaN
Week 24 (n=91, n=95)	0.82 0.1%	0.87 NaN
Week 28 (n=79, n=85)	0.79 0.1%	0.85 NaN
Week 32 (n=74, n=82)	0.79 0.1%	0.84 NaN
Week 36 (n=74, n=76)	0.79 0.1%	0.83 NaN
Week 40 (n=74, n=70)	0.79 0.1%	0.82 NaN
Week 44 (n=74, n=70)	0.79 0.1%	0.82 NaN
Week 48 (n=74, n=70)	0.79 0.1%	0.82 NaN
Week 52 (n=19, n=70)	0.76 0.1%	0.82 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.381
	Comments	p-value for equality of survival curves
	Method	Log Rank
	Comments	stratified log-rank test, conrolling for type of index mood episode
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.784
	Confidence Interval	(2-Sided) 95%; 0.454 to 1.354
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole/placebo; Cox's proportional hazards model, with type of index mood episode as stratification facto, and randomized treatment group as covariate.

4. Secondary Outcome

Title	Proportion of Participants Without Discontinuation for Any Reason in the Double-blind Relapse Assessment Phase (Phase 2)
Description	Proportion of Participants without Discontinuation Through Week 52(Kaplan-Meier's estimated survival rate).
Time Frame	Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52

Outcome Measure Data

Analysis Population Description

Randomized Participants (comprises all patients who are randomized in Phase 2). n= number of randomized participants evaluated at given time point.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	173	178
Week 0 (n=173, n=178)	0.95 0.1%	0.99 NaN
Week 2 (n=164, n=175)	0.90 0.1%	0.91 NaN
Week 4 (n=155, n=161)	0.84 0.1%	0.84 NaN
Week 6 (n=145, n=149)	0.79 0.1%	0.78 NaN
Week 8 (n=135, n=138)	0.71 0.1%	0.70 NaN
Week 12 (n=122, n=124)	0.61 0.1%	0.65 NaN
Week 16 (n=103, n=115)	0.55 0.1%	0.62 NaN
Week 20 (n=95, n=110)	0.53 0.1%	0.59 NaN
Week 24 (n=90, n=104)	0.46 0.1%	0.51 NaN
Week 28 (n=78, n=89)	0.41 0.1%	0.47 NaN
Week 32 (n=70, n=83)	0.38 0%	0.44 NaN
Week 36 (n=64, n=77)	0.36 0%	0.41 NaN
Week 40 (n=61, n=72)	0.34 0%	0.39 NaN
Week 44 (n=57, n=69)	0.33 0%	0.38 NaN
Week 48 (n=56, n=66)	0.32 0%	0.37 NaN
Week 52 (n=19, n=65)	0.25 0%	0.37 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.295
	Comments	p-value for equality of survival curves
	Method	Log Rank
	Comments	stratified Log-Rank Test, controlling for type of index mood episode
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.871
	Confidence Interval	(2-Sided) 95%; 0.672 to 1.128
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole/placebo; Cox's proportional hazards model, with type of index mood episode as stratification facto, and randomized treatment group as covariate.

5. Secondary Outcome

Title	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
Description	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.
Time Frame	Throughout Phase 2 (up to 52 weeks)

Outcome Measure Data

Analysis Population Description

The Phase 2 Safety Sample comprises all patients who are randomized into Phase 2 and take at least one dose of double-blind medication in Phase 2, as indicated on the study therapy form.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Deaths	0 0%	0 NaN
Treatment-Emergent SAEs	9 1.1%	5 NaN
Suicide-Related SAEs	0 0%	0 NaN
AEs Leading to Discontinuation of Study Medication	12 1.5%	14 NaN
Treatment-Emergent AEs	111 13.9%	124 NaN
Treatment-Emergent EPS-Related AEs	15 1.9%	28 NaN

6. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Body Weight, Phase 2
Description	Adjusted for index mood episode and baseline assessment
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants from the phase 2 Safety Sample who had body weight evaluation at baseline and week 52 LOCF.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	143	151
Mean (Standard Error) [kg]	-1.81 (0.48)	0.43 (0.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Week 52 LOCF
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	ANOVA (main effects=double-blind treatment, covariate=index mood episode) used for baseline comparisons. ANCOVA (main effects=double-blind treatment, covariates=index mood episode & baseline assessment) used for mean change from baseline comparisons
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatement Difference
	Estimated Value	2.24
	Confidence Interval	(2-Sided) 95%; 0.91 to 3.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Aripiprazole vs. placebo

7. Secondary Outcome

Title	Number of Participants Showing Clinically Relevant Weight Loss by Study Week
Description	Weight Loss of at least a 7% decrease from Baseline.
Time Frame	Weeks 12, 24, 36, 52

Outcome Measure Data

Analysis Population Description

Observed cases (OC) data set (actual observation at each visit), Last observation carried forward (LOCF) data set (data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit), and Overall, Phase 2 Safety Sample; n=number assessed at given time point.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Week 12 (n=105, 107)	7 0.9%	9 NaN
Week 24 (n=84, 87)	8 1%	9 NaN
Week 36 (n=54, 67)	10 1.3%	6 NaN
Week 52 (n=49, 56)	10 1.3%	6 NaN
Week 52 LOCF (n=143, 151)	22 2.8%	13 NaN
At Any Time (n=147, 154)	26 3.3%	19 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Week 52 LOCF
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; 0.29 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole/placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	At Any Time
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.194
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

8. Secondary Outcome

Title	Number of Participants Showing Clinically Relevant Weight Gain by Study Week
Description	Weight gain of at least a 7% increase from Baseline.
Time Frame	Weeks 12, 24, 36, 52

Outcome Measure Data

Analysis Population Description

Observed cases (OC) data set (actual observation at each visit), Last observation carried forward (LOCF) data set (data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit), and Overall, Phase 2 Safety Sample; n=number assessed at given time point.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Week 12 (n=105, 107)	2 0.3%	4 NaN
Week 24 (n=84, 87)	3 0.4%	10 NaN
Week 36 (n=54, 67)	5 0.6%	14 NaN
Week 52 (n=49, 56)	2 0.3%	7 NaN
Week 52 LOCF (n=143, 151)	5 0.6%	18 NaN
At Any Time (n=147, 154)	8 1%	27 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Week 52 LOCF
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	relative risk
	Estimated Value	3.41
	Confidence Interval	(2-Sided) 95%; 1.30 to 8.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

9. Secondary Outcome

Title	Adjusted Mean Change From Baseline in BMI by Study Week
Description	Adjusted for index mood episode and baseline assessment.
Time Frame	Baseline, Weeks 12, 24, 36, 52

Outcome Measure Data

Analysis Population Description

Observed cases (OC) data set (actual observation at each visit), Last observation carried forward (LOCF) data set (data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit), and Overall, Phase 2 Safety Sample; n=number assessed at given time point.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Baseline (n=143, 150)	30.77 (0.63)	30.13 (0.61)
Change from Baseline Week 12 (n=105, 107)	-0.39 (0.15)	-0.03 (0.15)
Change from Baseline Week 24 (n=84, 87)	-0.60 (0.20)	0.14 (0.20)
Change from Baseline Week 36 (n=54, 67)	-0.63 (0.33)	0.34 (0.30)
Change from Baseline Week 52 (n=49, 56)	-0.73 (0.37)	0.19 (0.34)
Change from Baseline Week 52 LOCF (n=143, 150)	-0.62 (0.17)	0.17 (0.17)
Highest Change from Baseline (n=143, 150)	-0.02 (0.15)	0.61 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.467
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA model, with double-blind treatment as main effects and index mood episode as covariate, is used for Baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95%; -2.37 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.19 to 1.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 36
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.08 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 52
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; -0.08 to 1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 52 (LOCF)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariates=index mood episode & baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.31 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Highest Change from baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariates=index mood episode & baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.23 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

10. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities Occurring During Double-Blind Treatment
Description	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.
Time Frame	Throughout the study, up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with ECG evaluation from the phase 2 Safety Sample (all patients who are randomized into Phase 2 and take at least one dose of double-blind medication in Phase 2, as indicated on the study therapy form.)

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	124	132
Tachycardia: ≥ 120 bpm and ↑ ≥ 15 bpm	1	1
Bradycardia: ≤ 50 bpm and ↓ 15 bpm	2	0
Sinus Tachycardia: ≥ 120 bpm and ↑ ≥ 15 bpm	1	0
Sinus Bradycardia: ≤ 50 bpm and ↓ 15 bpm	2	0
SPB: not present → present (see description)	0	0
VPB: not present → present (see description)	2	1
Supraventricular Tachycardia: not present→ present	0	0
Ventricular Tachycardia: not present → present	0	0
Atrial Fibrillation (AF): not present → present	0	0
AF With Rapid Ventricular Response	0	0
Atrial Flutter: not present → present	0	1
1st Degree A-V Block: PR ≥0.20 sec and ↑ ≥0.05 sec	0	0
2nd Degree A-V Block: not present → present	0	0
3rd Degree A-V Block: not present → present	0	0
Left Bundle Branch Block: not present → present	0	0
Right Bundle Branch Block: not present → present	6	4
Pre-excitation Syndrome: not present → present	0	0
Other Intraventricular Conduction: see description	0	0
Acute Infarction: not present → present	0	0
Subacute (recent) Infarction: not present→ present	0	0
Old Infarction: not present → present	1	0
Myocardial Ischemia: not present → present	0	0
Symmetrical T-Wave Inversions: not present→present	0	0
QTc Bazett: > 450 msec	5	6
QTc (.37): > 450 msec	0	0
QTc (.33): > 450 msec	0	1

11. Secondary Outcome

Title	Number of Participants With Potentially Clinically Relevant Vital Sign Abnormalities Occurring During Double-Blind Treatment
Description	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.
Time Frame	Up to 52 Weeks

Outcome Measure Data

Analysis Population Description

Phase 2 Safety Sample (all patients who are randomized into Phase 2 and take at least one dose of double-blind medication in Phase 2, as indicated on the study therapy form).

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Systolic BP, supine-Increase (n=160,168)	3 0.4%	1 NaN
Systolic BP, supine-Decrease (n=160,168)	7 0.9%	5 NaN
Systolic BP, standing-Increase (n=153, 157)	3 0.4%	0 NaN
Systolic BP, standing-Decrease (n=153,157)	2 0.3%	4 NaN
Diastolic BP, supine-Increase (n=160,168)	2 0.3%	0 NaN
Diastolic BP, supine-Decrease (n=160,168)	0 0%	3 NaN
Diastolic BP, standing-Increase (n=153,157)	6 0.8%	1 NaN
Diastolic BP, standing-Decrease (n=153,157)	0 0%	1 NaN
Heart Rate, supine-Increase (n=160,168)	0 0%	0 NaN
Heart Rate, supine-Decrease (n=160,168)	3 0.4%	0 NaN
Heart Rate, standing-Increase (n=153, 157)	4 0.5%	2 NaN
Heart Rate, standing-Decrease (n=153, 157)	1 0.1%	0 NaN

12. Secondary Outcome

Title	Number of Participants With Potentially Clinically Relevant Laboratory Abnormalities Occurring During Double-Blind Treatment (Phase 2)
Description	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)
Time Frame	Throughout Phase 2 of the study, up to Week 52

Outcome Measure Data

Analysis Population Description

Phase 2 safety sample

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
ALT ≥3 x ULN (n=151,157)	3	0
AST ≥3 x ULN (n=151, 157)	2	1
ALP ≥3 x ULN (n=151, 157)	0	0
LDH ≥3 x ULN (n=151, 158)	0	0
BUN ≥30 mg/dL (n=151, 158)	0	2
Creatine kinase (n=3, 1)	0	0
Creatinine ≥2.0 mg/dL (n=151, 157)	0	0
Uric acid (n=151, 157)	0	2
Bilirubin (total) ≥ 2.0 mg/dL (n=152, 157)	0	0
Prolactin (n=152, 158)	32	18
Cholesterol Total (n=151, 157)	22	28
Cholesterol Total (fasting) (n=126, 124)	17	25
Cholesterol Total (non-fasting) (n=68, 75)	9	7
Glucose Fasting Serum (n=126, 125)	15	13
HDL-C (n=151, 158)	53	38
HDL-C (fasting) (n=126, 125)	44	25
HDL-C (non-fasting) (n=68, 75)	23	19
LDL-C (n=151, 157)	17	26
LDL-C (fasting) (n=126, 124)	14	22
LDL-C (non-fasting) (n=68, 75)	7	5
Triglycerides (n=151, 157)	0	0
Triglycerides (fasting) (n=126, 124)	26	29
Triglycerides (non-fasting) (n=68, 75)	19	20
Sodium serum (n=152, 158)	1	0
Potassium serum (n=152, 158)	0	0
Chloride serum (n=152, 158)	0	0
Calcium (n=151, 157)	0	0
Hemoglobin ≤11.5 g/dL(m)/≤9.5 g/dL(f) (n=152, 156)	1	0
Hematocrit ≤37(m)/≤32(f) & 3 ↓from BL (n=152,156)	1	3
Leukocytes ≤2800 mm^3 or ≥16000 mm^3 (n=152, 156)	0	2
Eosinophils relative (calculated)≥10% (n=152, 156)	2	2
Neutrophils relative (calculated)≤15% (n=152, 156)	0	0
Platelets ≤75,000 mm3 or ≥700,000 mm3 (n=152,155)	0	0
Protein urine increase of ≥2 units (n=145, 152)	0	0
Glucose urine (n=149, 155)	0	0

13. Secondary Outcome

Title	Summary of Concomitant Medications, Phase 1
Time Frame	Phase 1 (9 to 24 Week Single-blind Stabilization Phase)

Outcome Measure Data

Analysis Population Description

Phase 1 Safety Sample (all patients who take at least one dose of singleblind aripiprazole in Phase 1, as indicated on the study therapy form).

Arm/Group Title	Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 1 (all subjects) - up to 24 weeks
Measure Participants	787
Any central nervous system Medication	550 69.1%
Analgesic	2 0.3%
Anesthetic, general	1 0.1%
Anesthetic, local	3 0.4%
Anticholinergic	98 12.3%
Antidepressant	12 1.5%
Antiepileptic	48 6%
Antimigraine prep	12 1.5%
Antipsychotic	20 2.5%
Anxiolytic	267 33.5%
Hypnotic & Sedative	206 25.9%
Opiod	78 9.8%
Other Analgesic & Antipyretic	253 31.8%
Other Nervous System Drug	1 0.1%
Psychostimulant	2 0.3%
Any extrapyramidal syndrome Medication	98 12.3%
Benztropine	98 12.3%

14. Secondary Outcome

Title	Summary of Concomitant Medications, Phase 2
Time Frame	Phase 2 (52 Week Double-blind Relapse Assessment Phase)

Outcome Measure Data

Analysis Population Description

Phase 2 Safety Sample (all patients who are randomized into Phase 2 and take at least one dose of double-blind medication in Phase 2, as indicated on the study therapy form).

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Any central nervous system Medication	120 15.1%	132 NaN
Anesthetic, local	1 0.1%	0 NaN
Anticholinergic	21 2.6%	25 NaN
Antidepressant	3 0.4%	1 NaN
Antiepileptic	8 1%	11 NaN
Antimigraine prep	1 0.1%	3 NaN
Antipsychotic	5 0.6%	3 NaN
Anxiolytic	63 7.9%	62 NaN
Hypnotic & Sedative	50 6.3%	41 NaN
Opiod	20 2.5%	14 NaN
Other Analgesic & Antipyretic	53 6.7%	66 NaN
Psychostimulant	0 0%	1 NaN
Any extrapyramidal syndrome Medication	25 3.1%	35 NaN
Benztropine	25 3.1%	35 NaN
Trihexyphenidyl	1 0.1%	1 NaN

15. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score
Description	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.
Time Frame	Baseline, Weeks 8, 24, 36, 52

Outcome Measure Data

Analysis Population Description

Observed cases (OC) data set (actual observation at each visit), Last observation carried forward (LOCF) data set (data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit). n=number of participants analyzed at timepoint.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Baseline (n=125, 128)	10.59 (0.12)	10.58 (0.12)
Change from Baseline at Week 8 (n=125, 124)	-0.20 (0.10)	0.05 (0.10)
Change from Baseline at Week 24 (n=85, 89)	-0.21 (0.13)	0.03 (0.13)
Change from Baseline at Week 36 (n=54, 67)	-0.38 (0.11)	-0.14 (0.10)
Change from Baseline at Week 52 (n=50, 56)	-0.35 (0.13)	-0.05 (0.12)
Change from Baseline at Week 52 LOCF (n=152, 161)	-0.22 (0.10)	0.02 (0.10)
Highest Change from Baseline (n=152, 161)	0.03 (0.12)	0.34 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.971
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANOVA
	Comments	ANOVA model, with double-blind treatment as main effects, is used for Baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 36
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 52
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 52 (LOCF)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.095
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariate=baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Highest change from Baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.061
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariate=baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripirazole - placebo

16. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score
Description	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.
Time Frame	Baseline, Weeks 8, 24, 36, 52

Outcome Measure Data

Analysis Population Description

Observed cases (OC) data set (actual observation at each visit), Last observation carried forward (LOCF) data set (data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit). n=number of participants analyzed at timepoint.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Baseline (n=125, 128)	0.21 (0.07)	0.14 (0.07)
Change from Baseline at Week 8 (n=124, 124)	-0.05 (0.05)	0.06 (0.06)
Change from Baseline at Week 24 (n=85, 89)	-0.01 (0.06)	0.04 (0.05)
Change from Baseline at Week 36 (n=54, 67)	-0.09 (0.08)	0.13 (0.07)
Change from Baseline at Week 52 (n=50, 56)	-0.11 (0.04)	-0.05 (0.04)
Change from Baseline at Week 52 LOCF (n=153, 161)	0.05 (0.06)	-0.01 (0.06)
Highest Change from Baseline (n=153, 161)	0.10 (0.07)	0.14 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.458
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANOVA
	Comments	ANOVA model, controlling for treatment, is used for baseline estimates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.07
	Confidence Interval	() 95%; -0.25 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 36
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at week 52
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 52 (LOCF)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.515
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariate=baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Highest Change from Baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.730
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariate=baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

17. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment,
Description	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.
Time Frame	Baseline, Weeks 8, 24, 36, 52

Outcome Measure Data

Analysis Population Description

Observed cases (OC) data set (actual observation at each visit), Last observation carried forward (LOCF) data set (data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit). n=number of participants analyzed at timepoint.

Arm/Group Title	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo	Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
Measure Participants	165	176
Baseline (n=125, 128)	0.22 (0.05)	0.27 (0.05)
Change from Baseline at Week 8 (n=125, 124)	-0.12 (0.05)	0.04 (0.05)
Change from Baseline at Week 24 (n=85, 89)	-0.09 (0.05)	-0.06 (0.05)
Change from Baseline at Week 36 (n=54, 67)	-0.18 (0.05)	-0.18 (0.04)
Change from Baseline at Week 52 (n=50, 56)	-0.20 (0.04)	-0.17 (0.04)
Change from Baseline at Week 52 LOCF (n=153, 161)	-0.11 (0.04)	-0.05 (0.04)
Highest Change from Baseline (n=153, 161)	-0.02 (0.05)	0.15 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.435
	Comments	Means, mean differences, 95% confidence intervals for the differences, and the p-values are based on ANOVA/ANCOVA model.
	Method	ANOVA
	Comments	ANOVA, controlling for treatment, used for baseline estimates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 36
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from baseline at Week 52
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Change from Baseline at Week 52 (LOCF)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.358
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariate=baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Phase 2 Double-Blind Treatment: Lamotrigine + Placebo, Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Comments	Highest Change from Baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	Means, treatment differences between aripiprazole and placebo, 95% confidence intervals for the differences and the p-values for treatment comparisons are based on ANOVA/ANCOVA model.
	Method	ANCOVA
	Comments	ANCOVA (main effects=double-blind treatment, covariate=baseline assessment) used for mean change from baseline comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	aripiprazole - placebo

Adverse Events

Arm/Group Title	Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole		Phase 2 Double-Blind Treatment: Lamotrigine + Placebo		Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
Arm/Group Description	Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 1 (all subjects) - up to 24 weeks		Lamotrigine 100-200 mg/day, Placebo 0 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks		Lamotrigine 100-200 mg/day, Aripiprazole 10-30 mg/day: tablets, oral, once daily, Phase 2 - up to 52 weeks.
All Cause Mortality
	Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole		Phase 2 Double-Blind Treatment: Lamotrigine + Placebo		Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole		Phase 2 Double-Blind Treatment: Lamotrigine + Placebo		Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/787 (4.1%)		9/165 (5.5%)		5/176 (2.8%)
Blood and lymphatic system disorders
ANAEMIA	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
Cardiac disorders
CARDIAC DISORDER	0/787 (0%)		0/165 (0%)		1/176 (0.6%)
VENTRICULAR FIBRILLATION	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
WOLFF-PARKINSON-WHITE SYNDROME	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
Gastrointestinal disorders
INGUINAL HERNIA	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
GASTRITIS EROSIVE	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
MALLORY-WEISS SYNDROME	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
General disorders
CHEST PAIN	3/787 (0.4%)		2/165 (1.2%)		0/176 (0%)
NON-CARDIAC CHEST PAIN	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
Injury, poisoning and procedural complications
HEAD INJURY	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
INTENTIONAL OVERDOSE	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
ROAD TRAFFIC ACCIDENT	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
Metabolism and nutrition disorders
OBESITY	0/787 (0%)		0/165 (0%)		1/176 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
VULVAL CANCER	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
UTERINE LEIOMYOMA	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
Nervous system disorders
AKATHISIA	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
DIZZINESS	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
ALTERED STATE OF CONSCIOUSNESS	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
Pregnancy, puerperium and perinatal conditions
PREGNANCY	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
Psychiatric disorders
MANIA	3/787 (0.4%)		0/165 (0%)		0/176 (0%)
ANXIETY	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
AGITATION	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
DEPRESSION	3/787 (0.4%)		0/165 (0%)		1/176 (0.6%)
PANIC ATTACK	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
BIPOLAR DISORDER	2/787 (0.3%)		0/165 (0%)		0/176 (0%)
COMPLETED SUICIDE	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
SUICIDAL IDEATION	8/787 (1%)		0/165 (0%)		0/176 (0%)
BIPOLAR I DISORDER	2/787 (0.3%)		2/165 (1.2%)		1/176 (0.6%)
DEPRESSIVE SYMPTOM	2/787 (0.3%)		0/165 (0%)		0/176 (0%)
HOMICIDAL IDEATION	2/787 (0.3%)		0/165 (0%)		0/176 (0%)
MENTAL STATUS CHANGES	0/787 (0%)		0/165 (0%)		1/176 (0.6%)
Renal and urinary disorders
NEPHROLITHIASIS	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
Reproductive system and breast disorders
MENSTRUAL DISORDER	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
OVARIAN CYST RUPTURED	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
Social circumstances
PHYSICAL ASSAULT	1/787 (0.1%)		0/165 (0%)		0/176 (0%)
Vascular disorders
HYPERTENSION	0/787 (0%)		1/165 (0.6%)		0/176 (0%)
Other (Not Including Serious) Adverse Events
	Phase 1: Single-Blind Treatment, Lamotrigine + Aripiprazole		Phase 2 Double-Blind Treatment: Lamotrigine + Placebo		Phase 2 Double-Blind Treatment: Lamotrigine + Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	545/787 (69.3%)		61/165 (37%)		74/176 (42%)
Gastrointestinal disorders
NAUSEA	103/787 (13.1%)		6/165 (3.6%)		7/176 (4%)
VOMITING	40/787 (5.1%)		1/165 (0.6%)		1/176 (0.6%)
DRY MOUTH	44/787 (5.6%)		3/165 (1.8%)		4/176 (2.3%)
General disorders
FATIGUE	74/787 (9.4%)		1/165 (0.6%)		5/176 (2.8%)
Infections and infestations
URINARY TRACT INFECTION	35/787 (4.4%)		9/165 (5.5%)		5/176 (2.8%)
UPPER RESPIRATORY TRACT INFECTION	34/787 (4.3%)		13/165 (7.9%)		12/176 (6.8%)
Musculoskeletal and connective tissue disorders
BACK PAIN	26/787 (3.3%)		5/165 (3%)		9/176 (5.1%)
Nervous system disorders
HEADACHE	92/787 (11.7%)		13/165 (7.9%)		8/176 (4.5%)
SEDATION	62/787 (7.9%)		3/165 (1.8%)		1/176 (0.6%)
AKATHISIA	196/787 (24.9%)		10/165 (6.1%)		19/176 (10.8%)
DIZZINESS	40/787 (5.1%)		3/165 (1.8%)		2/176 (1.1%)
SOMNOLENCE	42/787 (5.3%)		0/165 (0%)		1/176 (0.6%)
Psychiatric disorders
ANXIETY	73/787 (9.3%)		6/165 (3.6%)		13/176 (7.4%)
INSOMNIA	138/787 (17.5%)		19/165 (11.5%)		13/176 (7.4%)
AGITATION	65/787 (8.3%)		8/165 (4.8%)		11/176 (6.3%)
RESTLESSNESS	55/787 (7%)		2/165 (1.2%)		3/176 (1.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.