Trial Outcomes & Findings for An Evaluation Of BW430C (Lamotrigine) Versus Placebo In The Prevention Of Mood Episodes In Bipolar I Disorder Patients (NCT NCT00550407)

NCT ID: NCT00550407

Last Updated: 2016-11-23

Results Overview

The time from randomization to the time at which the participant was withdrawn from the Double-Blind Phase of the study for any reason was measured. No data are reported for the Lamotrigine group because of an incalculable confidence interval. See the outcome measure entitled "Number of Participants with a Withdrawal Event" for data regarding the number of participants who withdrew from the study.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 215 participants
• Primary outcome timeframe: Randomization to Study Withdrawal (up to Week 26)
• Results posted on: 2016-11-23

Participant Flow

Participants whose symptoms of mood episodes were stabilized with lamotrigine in the Preliminary Phase (Clinical Global Impressions of Severity score of 3 [mild] or less for at least 4 consecutive weeks, and lamotrigine given as monotherapy for at least 1 week before the start of the Randomized Phase) were randomized to placebo or lamotrigine.

Participant milestones

Measure	Lamotrigine 25-200 mg The dose of lamotrigine was increased gradually in the dose range of 25-200 milligrams (mg)/day, while the doses of other medications for bipolar disorder were decreased gradually	Placebo Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
8-16 Week Preliminary (Open-Label) Phase STARTED	215	0	0
8-16 Week Preliminary (Open-Label) Phase COMPLETED	103	0	0
8-16 Week Preliminary (Open-Label) Phase NOT COMPLETED	112	0	0
26-Week Randomized Phase STARTED	0	58	45
26-Week Randomized Phase COMPLETED	0	15	21
26-Week Randomized Phase NOT COMPLETED	0	43	24

Reasons for withdrawal

Measure	Lamotrigine 25-200 mg The dose of lamotrigine was increased gradually in the dose range of 25-200 milligrams (mg)/day, while the doses of other medications for bipolar disorder were decreased gradually	Placebo Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
8-16 Week Preliminary (Open-Label) Phase Adverse Event	55	0	0
8-16 Week Preliminary (Open-Label) Phase Lack of Efficacy	39	0	0
8-16 Week Preliminary (Open-Label) Phase Protocol Violation	1	0	0
8-16 Week Preliminary (Open-Label) Phase Defined Stopping Criteria Reached	1	0	0
8-16 Week Preliminary (Open-Label) Phase Lost to Follow-up	1	0	0
8-16 Week Preliminary (Open-Label) Phase Investigator Discretion	8	0	0
8-16 Week Preliminary (Open-Label) Phase Withdrew Consent	6	0	0
8-16 Week Preliminary (Open-Label) Phase Continuation Criteria Not Met	1	0	0
26-Week Randomized Phase Adverse Event	0	5	2
26-Week Randomized Phase Lack of Efficacy	0	36	19
26-Week Randomized Phase Investigator Discretion	0	1	0
26-Week Randomized Phase Withdrawal by Subject	0	1	3

Baseline Characteristics

An Evaluation Of BW430C (Lamotrigine) Versus Placebo In The Prevention Of Mood Episodes In Bipolar I Disorder Patients

Baseline characteristics by cohort

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.	Total n=103 Participants Total of all reporting groups
Age, Continuous	43.1 years STANDARD_DEVIATION 12.68 • n=5 Participants	42.4 years STANDARD_DEVIATION 11.79 • n=7 Participants	42.8 years STANDARD_DEVIATION 12.25 • n=5 Participants
Sex: Female, Male Female	31 Participants n=5 Participants	27 Participants n=7 Participants	58 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	18 Participants n=7 Participants	45 Participants n=5 Participants
Race/Ethnicity, Customized Asian-Japanese Heritage	58 participants n=5 Participants	44 participants n=7 Participants	102 participants n=5 Participants
Race/Ethnicity, Customized Asian-East Asian Heritage	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: Full Analysis Set in Randomized (double-blind) Phase (FAS2): participants who received at least one dose of study medication in the Randomized Phase (RP) and had at least one post-treatment efficacy assessment in the RP. The upper limit of the confidence interval was not calculable for the Lamotrigine group due to an insufficient number of events.

The time from randomization to the time at which the participant was withdrawn from the Double-Blind Phase of the study for any reason was measured. No data are reported for the Lamotrigine group because of an incalculable confidence interval. See the outcome measure entitled "Number of Participants with a Withdrawal Event" for data regarding the number of participants who withdrew from the study.

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Time to Withdrawal From Study	67.5 days Interval 32.0 to 127.0	—

SECONDARY outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: FAS2. In the Lamotrigine 200 mg group, the estimated median TIME was not calculable because the probability of not reaching TIME remained greater than 0.50 throughout the study.

The TIME was defined as the time from entry into the Randomized Phase to the time of the first prescription of any additional pharmacotherapy or electroconvulsive therapy (ECT) determined by the Investigator to be necessary for treatment of a relapse or recurrence of depression or the recurrence of a manic, hypomanic, or mixed episode, whichever occurred first. Categorization as a manic, hypomanic, or mixed episode was left to the Investigator's discretion. See the outcome measure entitled "Number of Participants with Intervention for Any Mood Episode" for data related to TIME.

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Time to Intervention for Any Mood Episode (TIME)	109.0 days Interval 43.0 to 141.0	—

SECONDARY outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: FAS2. In the Lamotrigine 200 mg group, the estimated median TIDep was not calculable because the probability of not reaching TIDep remained greater than 0.50 throughout the study. The upper limit of the confidence interval was not calculable for the Placebo group due to an insufficient number of events.

The TIDep was defined as the time from entry into the Randomized Phase to the time of the first prescription of any additional pharmacotherapy or ECT determined by the Investigator to be necessary for treatment of a relapse or recurrence of depression episode. No data are being presented for either treatment group. See the outcome measure entitled "Number of Participants with Intervention for Depressive Episode" for data related to TIDep.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: FAS2. In both groups, the estimated median TIMan was not calculable because the probability of not reaching TIMan remained greater than 0.50 throughout the study.

The TIMan was defined as the time from entry into the Randomized Phase to the time of the first prescription of any additional pharmacotherapy or ECT determined by the Investigator to be necessary for treatment of the relapse or recurrence of a manic, hypomanic, or mixed episode. No data are being presented for either treatment group. See the outcome measure entitled "Number of Participants with Intervention for a Manic, Hypomanic, or Mixed Episode" for data related to TIMan.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 26/Withdrawal

Population: FAS2

The CGI-I is a 7-point scale that assessed the participant's global improvement compared to his/her condition at study entry whether or not, in the judgement of the Investigator, it was due entirely to drug treatment; 0=not assessed, 1= very much improved to 7= very much worse.

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Clinical Global Impressions of Improvement (CGI-I) at Week 26/Withdrawal (Randomized Phase)	3.5 points on a scale Standard Deviation 1.50	2.4 points on a scale Standard Deviation 1.29

SECONDARY outcome

Timeframe: Week 16/Withdrawal

Population: Full Analysis Set in the Preliminary Phase (FAS1): all participants who received at least one dose of study medication for the Preliminary Phase and underwent at least one efficacy assessment after receiving the study medication in the Preliminary Phase. Nine participants in the Lamotrigine 25-200 mg group have no data for the CGI-I.

The CGI-I is a 7-point scale that assessed the participant's global improvement compared to his/her condition at study entry whether or not, in the judgement of the Investigator, it was due entirely to drug treatment; 0=not assessed, 1= very much improved to 7= very much worse.

Outcome measures

Measure	Placebo n=206 Participants Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Clinical Global Impressions of Improvement (CGI-I) at Week 16/Withdrawal (Preliminary Phase)	3.1 points on a scale Standard Deviation 1.56	—

SECONDARY outcome

Timeframe: Baseline and Week 26/Withdrawal

Population: FAS2

The CGI-S is a 7-point scale that assessed the participant's severity of illness based on the total clinical experience of the Investigator with this particular population; 0=not assessed, 1= normal, not at all ill to 7= among the most extremely ill participants. Change from baseline was calculated as the Week 26/Withdrawal value minus the baseline value (at the time of randomization).

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Change From Baseline in Clinical Global Impressions of Severity (CGI-S) Scores at Week 26/Withdrawal (Randomized Phase)	1.0 points on a scale Standard Deviation 1.19	0.4 points on a scale Standard Deviation 1.25

SECONDARY outcome

Timeframe: Baseline and Week 16/Withdrawal

Population: FAS1. Nine participants in the Lamotrigine 25-200 mg group have no data for the CGI-S at Week 16/Withdrawal.

The CGI-S is a 7-point scale that assessed the participant's severity of illness based on the total clinical experience of the Investigator with this particular population; 0=not assessed, 1= normal, not at all ill to 7= among the most extremely ill participants. Change from baseline was calculated as the Week 16/Withdrawal value minus the baseline value (at Week 0 of the Preliminary Phase).

Outcome measures

Measure	Placebo n=206 Participants Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Change From Baseline in Clinical Global Impressions of Severity (CGI-S) Scores at Week 16/Withdrawal (Preliminary Phase)	-0.7 points on a scale Standard Deviation 1.39	—

SECONDARY outcome

Timeframe: Baseline and Week 26/Withdrawal

Population: FAS2

The HAMD-17 is a 17-item questionnaire that detects change and measures illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2 with the total HAMD-17 score ranging from 0 (not ill) to 52 (severely ill). Change from baseline was calculated as the Week 26/Withdrawal value minus the baseline value (at the time of randomization).

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Change From Baseline in Hamilton Rating Scale for Depression (HAMD-17) Scores at Week 26/Withdrawal (Randomized Phase)	5.4 points on a scale Standard Deviation 7.39	2.7 points on a scale Standard Deviation 7.77

SECONDARY outcome

Timeframe: Baseline and Week 16/Withdrawal

Population: FAS1. Nine participants in the Lamotrigine 25-200 mg group have no data for the HAMD-17 at Week 16/Withdrawal.

The HAMD-17 is a 17-item questionnaire that detects change and measures illness severity. Individual items are rated on a scale of 0-4, and 0-2, with the total HAMD-17 score ranging from 0 (not ill) to 52 (severely ill). Change from baseline was calculated as the Week 16/Withdrawal value minus the baseline value (at Week 0 of the Preliminary Phase).

Outcome measures

Measure	Placebo n=206 Participants Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Change From Baseline in Hamilton Rating Scale for Depression (HAMD-17) Scores at Week 16/Withdrawal (Preliminary Phase)	-4.1 points on a scale Standard Deviation 9.14	—

SECONDARY outcome

Timeframe: Baseline and Week 26/Withdrawal

Population: FAS2

The YMRS is an 11-item questionnaire that detects change and measures illness severity. Individual items are rated on a scale of 0-8 and 0-4, with the total YMRS score ranging from 0 (not ill) to 60 (severely ill). Change from baseline was calculated as the Week 26/Withdrawal value minus the baseline value (at the time of randomization).

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Change From Baseline in Young Mania Rating Scale (YMRS) Total Scores at Week 26/Withdrawal (Randomized Phase)	2.2 points on a scale Standard Deviation 6.59	1.0 points on a scale Standard Deviation 5.67

SECONDARY outcome

Timeframe: Baseline and Week 16/Withdrawal

Population: FAS1. Nine participants in the Lamotrigine 25-200 mg group have no data for the HAMD-17 at Week 16/Withdrawal.

The YMRS is an 11-item questionnaire that detects change and measures illness severity. Individual items are rated on a scale of 0-8 and 0-4, with the total YMRS score ranging from 0 (not ill) to 60 (severely ill). Change from baseline was calculated as the Week 16/Withdrawal value minus the baseline value (at Week 0 of the Preliminary Phase).

Outcome measures

Measure	Placebo n=206 Participants Matching placebo	Lamotrigine 200 mg Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Change From Baseline in Young Mania Rating Scale (YMRS) Total Scores at Week 16/Withdrawal (Preliminary Phase)	0.4 points on a scale Standard Deviation 10.45	—

POST_HOC outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: FAS2

The number of participants who withdrew from the study was measured. This outcome measure was added post-hoc because no data are being reported for the Lamotrigine group regarding time to study withdrawal. See the primary outcome measure for time to study withdrawal data for the Placebo group. Data from participants who had not withdrawn were defined as censored.

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Number of Participants With a Withdrawal Event Withdrawal Event	43 participants	24 participants
Number of Participants With a Withdrawal Event Censored	15 participants	21 participants

POST_HOC outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: FAS2

The number of participants with intervention for any mood episode was measured. The necessity of the intervention was determined by the Investigator's discretion. This outcome measure was added post-hoc because no data are being reported for the Lamotrigine group regarding time to intervention for any mood episode (TIME). See the outcome measure for TIME for data for the Placebo group. Data from participants who had not met TIME were defined as censored.

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Number of Participants With Intervention for Any Mood Episode Censored	21 participants	25 participants
Number of Participants With Intervention for Any Mood Episode Intervention Event	37 participants	20 participants

POST_HOC outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: FAS2

The number of participants with intervention for depressive episode was measured. The necessity of the intervention was determined by the Investigator's discretion. This outcome measure was added post-hoc because no data are being reported for the Placebo or Lamotrigine groups regarding time to intervention for depressive episode (TIDep). Data from participants who had not met TIDep were defined as censored.

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Number of Participants With Intervention for Depressive Episode Intervention Event	27 participants	15 participants
Number of Participants With Intervention for Depressive Episode Censored	31 participants	30 participants

POST_HOC outcome

Timeframe: Randomization to Study Withdrawal (up to Week 26)

Population: FAS2

The number of participants with intervention for a manic, hypomanic, or mixed episode was measured. The necessity of the intervention was determined by the Investigator's discretion. This outcome measure was added post-hoc because no data are being reported for the Placebo or Lamotrigine groups regarding time to intervention for manic, hypomanic, or mixed episode (TIMan). Data from participants who had not met TIMan were defined as censored.

Outcome measures

Measure	Placebo n=58 Participants Matching placebo	Lamotrigine 200 mg n=45 Participants Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Number of Participants With Intervention for a Manic, Hypomanic, or Mixed Episode Intervention Event	10 participants	5 participants
Number of Participants With Intervention for a Manic, Hypomanic, or Mixed Episode Censored	48 participants	40 participants

Adverse Events

Lamotrigine 25-200 mg

Serious events: 14 serious events

Other events: 84 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 17 other events

Deaths: 0 deaths

Lamotrigine 200 mg

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Measure	Lamotrigine 25-200 mg n=215 participants at risk The dose of lamotrigine was increased gradually in the dose range of 25-200 milligrams (mg)/day, while the doses of other medications for bipolar disorder were decreased gradually	Placebo n=58 participants at risk Matching placebo	Lamotrigine 200 mg n=45 participants at risk Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Psychiatric disorders Mania	3.7% 8/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	1.7% 1/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Psychiatric disorders Bipolar I disorder	0.93% 2/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Psychiatric disorders Affect lability	0.47% 1/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Psychiatric disorders Suicide ideation	0.47% 1/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Psychiatric disorders Suicide attempt	0.47% 1/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Nervous system disorders Altered state of consciousness	0.47% 1/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Skin and subcutaneous tissue disorders Drug eruption	0.47% 1/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	2.2% 1/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Psychiatric disorders Completed suicide	0.47% 1/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.

Other adverse events

Measure	Lamotrigine 25-200 mg n=215 participants at risk The dose of lamotrigine was increased gradually in the dose range of 25-200 milligrams (mg)/day, while the doses of other medications for bipolar disorder were decreased gradually	Placebo n=58 participants at risk Matching placebo	Lamotrigine 200 mg n=45 participants at risk Lamotrigine 200 mg once a day. The dose may have been reduced to 100 mg/day for safety reasons at the discretion of the investigator/subinvestigator. The use of other medications for bipolar disorder was prohibited.
Infections and infestations Nasopharyngitis	22.8% 49/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	22.4% 13/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	24.4% 11/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Nervous system disorders Headache	10.2% 22/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	3.4% 2/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	4.4% 2/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Gastrointestinal disorders Nausea	7.9% 17/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	3.4% 2/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Nervous system disorders Dizziness	7.4% 16/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	1.7% 1/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	2.2% 1/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Gastrointestinal disorders Constipation	5.1% 11/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	5.2% 3/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	4.4% 2/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Gastrointestinal disorders Diarrhoea	5.1% 11/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	1.7% 1/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/215 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	0.00% 0/58 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.	6.7% 3/45 Adverse events (AEs) and serious adverse events (SAEs) were collected in the Safety Population (SP). The SP is defined for the Preliminary and Randomized Phases as all participants who received at least one dose of study medication for each phase.

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