Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
This registration study in China is a multi-centre, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of lamotrigine in the prevention of recurrence/relapse of mood episodes in subjects with bipolar I disorder. Subjects are bipolar I disorder patients with recent/current manic, hypomanic, mixed or depressive episode. The study will include an open-label phase and a randomized phase. During the open-label phase, subjects will have lamotrigine monotherapy or combination therapy escalation. The target dose of lamotrigine is 200 milligram (mg)/day monotherapy. The duration of treatment in the open-label phase will last 6-16 weeks, until subjects reach a stable dose of lamotrigine. Beginning at week 7 of the open-label phase, subjects who have reached a stable dose of lamotrigine and met response criteria, defined as maintaining a Clinical Global Impression of Severity (CGI-S) score <= 3 for at least 4 continuous weeks and maintaining lamotrigine 200 mg/day monotherapy for at least 1 week, will be eligible to enroll in the double-blind phase of the study. Subjects who have not met response criteria after 16 weeks of participation in the open-label phase will be withdrawn from the study. Subjects will have lamotrigine 200 mg/day monotherapy for at least 1 week prior to randomization. Subjects who have met randomization requirements will be randomized 1:1 to lamotrigine 200 mg/day or placebo for 36 weeks double-blind treatment. After randomization, subjects will be assessed at weekly intervals for the first month, biweekly intervals for the second month, and then at monthly intervals for up to 36 weeks of double-blind treatment. The primary endpoint will be TIME, defined as the time to intervention (addition of pharmacotherapy or electroconvulsive therapy [ECT]) for any mood episode (relapse or recurrence of a depressive, manic, hypomanic or mixed episode) after randomization. The secondary endpoints will include time to intervention for manic, hypomanic or mixed episode (TIMan) and time to intervention for depressive episode (TIDep).The scores on the Hamilton Depression (HAMD), Young Mania Rating Scale (YMRS), CGI-I, CGI-S and Global Assessment Scale (GAS) will be used as indicators for both intensity and duration of mood symptoms during this phase. Subjects who withdraw early from the study prior to week 36 or reach TIME will have a follow-up visit 14 days after the last dose of investigational drug.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lamotrigine CD | Experimental | lamotrigine chewable dispersible tablets 25mg, 50mg, 100mg |
|
| Placebo | Placebo Comparator | Placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lamotrigine | Drug | in the double blind phase, lamotrigine 200mg/day will be used among half of eligible subjects after randomization |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Intervention for Any Mood Episode (TIME) | TIME is defined as being the time from entry into the randomized double-blind 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 and/or recurrence of a depressive, manic, hypomanic or mixed episode, whichever occurs first. TIME was measured relative to randomization date. Par. prematurely discontinued from the study prior to reaching the TIME event were censored at the time of discontinuation. Analysis was performed using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. | 36 weeks (wks) |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Intervention for Manic, Hypomanic or Mixed Episode (TIMan) | TIMan was analyzed using using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. Par. prematurely discontinued from the study prior to reaching the event were censored at the time of discontinuation. |
Not provided
Inclusion Criteria:
For open label phase
Subjects must be able to effectively communicate with study personnel, have the ability to comprehend the key components of the Inform Consent Form and must provide written informed consent to participate in the study prior to any study-specific assessments or procedures.
An in-patient or out-patient (male or female) and aged >=18 years old.
Disease to be studied: Has a diagnosis of the following disease as defined by DSM-IV criteria currently or within 60 days:
a)Bipolar I Disorder, most recent episode depressed (296.5x); b)Bipolar I Disorder, most recent episode hypomanic (296.40); c)Bipolar I Disorder, most recent episode manic (296.4x); d)Bipolar I Disorder, most recent episode mixed (296.6x)
The subject who has a diagnose of "bipolar I disorder, most recent episode depressed (296.5x)" must meet the following criteria:
Has at least one well documented manic, hypomanic or mixed episode, as defined by DSM-IV criteria, within 3 years of enrolment ; The duration of recent/current depressive episode is at least 2 weeks but not longer than 12 months prior to enrolment; For subject with currently experiencing a depressive episode, he/she must have a minimum total score of 18 on the HAMD-17 at s screening.
- The subject who has a diagnosis of "bipolar I disorder, most recent episode hypomanic (296.40)" or "bipolar I disorder, most recent episode manic (296.4x)" or "bipolar I disorder, most recent episode mixed (296.6x)" must meet the following criteria: Has had at least one well documented additional manic, hypomanic or mixed episode and one depressed episode, as defined by DSM-IV criteria, within 3 years of enrolment; Has a duration of the index manic episode of at least 1 week (unless hospitalised) or hypomanic episode of at least 4 days or mixed episode of at least 1 week. In neither case should the index episode be more than 12 months in duration; If the subject's index episode is the subject's initial/current manic mood event, subject must have a minimum score of 10 on the first 11 items of the YMRS at screening; If the subject's index episode is the subject's initial/current mixed mood event, subject must have a minimum score of 10 on the first 11 items of the YMRS, and have a minimum score of 18 on the HAMD-17 at screening.
For randomized double-blind phase
Exclusion Criteria:
For open label
For randomized double blind phase
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Guangzhou | Guangdong | 510180 | China | ||
| GSK Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35909213 | Derived | Zhang L, Zhang H, Lv LX, Tan Q, Xu X, Hu J, Zi L, Cooper J, Phansalkar A, Wang G. A randomised, double-blind, placebo-controlled study to evaluate the safety and efficacy of lamotrigine in the maintenance treatment of Chinese adult patients with bipolar I disorder. Int J Bipolar Disord. 2022 Aug 1;10(1):20. doi: 10.1186/s40345-022-00266-4. |
Not provided
Not provided
420 participants entered into OLP and received at least one dose of study medication. Of these 420 participants, 264 were randomized into RDP.
The study consisted of 4 phases: screen phase (<2 weeks[W]), open-label phase (OLP) (Up to 16 W, lamotrigine monotherapy (LM) or combination therapy escalated to a target dose of LM 200 milligrams [mg]/day[D]), randomized double-blind phase (RDP) (up to 36 W, lamotrigine 200 mg/day or placebo) and follow-up visit (14 days after the last dose).
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Open Label Lamotrigine 200 mg/Day | Participants (Par.) received lamotrigine escalated to a target dose of lamotrigine 200mg/day monotherapy for 6 weeks to 16 weeks. If needed, concomitant psychotropic medications were permitted during this phase however medications were discontinued at least 1 week before entering into the double-blind phase. |
| FG001 | Randomized Placebo | Participants who reached a stable dose of lamotrigine and met response criteria, defined as a Clinical Global Impression of Severity (CGI-S) score <= 3 maintained for at least 4 continuous weeks and lamotrigine 200 mg/day monotherapy maintained for at least 1 week during open label phase, were enrolled in the double-blind phase of the study. Participants received placebo for 36 weeks. |
| FG002 | Randomized Lamotrigine 200 mg/Day | Participants who reached a stable dose of lamotrigine and met response criteria, defined as a CGI-S score <= 3 maintained for at least 4 continuous weeks and lamotrigine 200 mg/day monotherapy maintained for at least 1 week during open label phase, were enrolled in the double-blind phase of the study. Participants received lamotrigine 200 mg/day for 36 weeks. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Open Label Phase |
|
| |||||||||||||||||||||
| Randomized Phase |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Open Label Lamotrigine 200 mg/Day | Participants (Par.) received lamotrigine escalated to a target dose of lamotrigine 200 mg/day monotherapy for 6 weeks to 16 weeks. If needed, concomitant psychotropic medications were permitted during this phase however medications were discontinued at least 1 week before entering into the double-blind phase. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Data is presented for Open Label Phase. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Intervention for Any Mood Episode (TIME) | TIME is defined as being the time from entry into the randomized double-blind 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 and/or recurrence of a depressive, manic, hypomanic or mixed episode, whichever occurs first. TIME was measured relative to randomization date. Par. prematurely discontinued from the study prior to reaching the TIME event were censored at the time of discontinuation. Analysis was performed using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. | Randomized (RD) Full analysis population: comprised of all randomized par. who took at least one dose of study medication and had at least one post-baseline efficacy/health outcomes assessment during randomized double-blind phase. "NA" implies no data are available. Only those par. with available data at indicated time points were analyzed. | Posted | Median | 95% Confidence Interval | Days | 36 weeks (wks) |
On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study treatment and until the follow up contact (up to Study Day 230).
On-treatment SAEs and non-serious AEs were reported for the Safety population consisted of all participants who received at least one dose of study drug.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Randomized Placebo | Participants who reached a stable dose of lamotrigine and met response criteria, defined as a Clinical Global Impression of Severity (CGI-S) score <= 3 maintained for at least 4 continuous weeks and lamotrigine 200 mg/day monotherapy maintained for at least 1 week during open label phase, were enrolled in the double-blind phase of the study. Participants received placebo for 36 weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mania | Psychiatric disorders | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | MedDRA | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| GSK Response Center | GlaxoSmithKline | 866-435-7343 |
Not provided
| ID | Term |
|---|---|
| D001714 | Bipolar Disorder |
| ID | Term |
|---|---|
| D000068105 | Bipolar and Related Disorders |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| D000077213 | Lamotrigine |
| ID | Term |
|---|---|
| D014227 | Triazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Placebo | Drug | Placebo |
|
| 36 weeks |
| Time to Intervention for Depressive Episode (TIDep) | TIDep was analyzed using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. Par. prematurely discontinued from the study prior to reaching the event were censored at the time of discontinuation. | 36 weeks |
| Overall Survival in Study (TIME-SIS). | TIME-SIS was defined as the time to intervention (addition of pharmacotherapy or ECT) for any mood episode, or to the time when the participant is withdrawn for any reason after randomization. The premature discontinuation of a participant prior to reaching TIME, for any reason, was treated as an event related to bipolar disorder. All participants prematurely discontinued prior to the TIME event in this analysis were to be assumed to have reached TIME. TIMS-SIS was analyzed using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. Par. prematurely discontinued from the study prior to reaching the event were censored at the time of discontinuation. | 36 weeks |
| Change From Baseline in Clinical Global Impression of Improvements (CGI-I) | The CGI-I is a 7-point scale where investigator were asked to assess the participant's illness at the time of assessment (improved or worsened) relative to a baseline state. In this scale, 1= very much improved; 2= much improved; 3= minimally improved; 4= no change; 5= minimally worse; 6= much worse; or 7= very much worse. Analysis was performed using Analysis of covariance with covariates of site, CGI-S baseline score and treatment. In presented Last-observation-carried-forward datasets, the last non-missing on therapy (OT) score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. Baseline value was defined as the last non-missing values at or prior to the randomization. Change from baseline at the time point of interest was calculated by subtracting the baseline values from the individual post-baseline values. If either baseline or post-baseline value was missing, the change from baseline was set to missing. | Baseline and up to 36 weeks |
| Change From Baseline in Clinical Global Impression of Severity (CGI-S) | The CGI-S is a 7-point scale where investigator were asked to rate the severity of the participant's illness at the time of assessment on severity of mental illness, where 1= normal, and 7= extremely ill. Data was collected on Weeks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32 and 36. Analysis performed using Analysis of Covariance (ANCOVA) with covariates of site, CGI-S baseline score (Open label phase), treatment and CGI-S baseline score. In presented Last observation carried forward (LOCF) datasets, last non-missing on therapy score prior to TIME was carried forward to estimate missing data points for remaining study visits of treatment period. The baseline value was defined as last non-missing values at or prior to the randomization. The change from baseline at the time point of interest was calculated by subtracting the baseline values from individual post-baseline values. If either the baseline or post-baseline value was missing, the change from baseline was set to missing as well. | Baseline and up to 36 weeks |
| Change From Baseline in Hamilton Depression Rating Scale (HAMD) | HAMD consists of 17 items: depressed mood, feelings of guilt, suicide, insomnia-early, middle, late, work and activities, retardation, agitation, anxiety psychic, anxiety somatic, somatic symptoms gastro-intestinal, general somatic symptoms, hypochondriasis, loss of weight, and insight. Investigators rated par. from 0 to 4 (or 2) for these items. Total score is sum of all subscales (0 to 52, higher is worse). Data was collected on Wks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32, 36. Analysis was performed using ANCOVA with covariates of site, CGI-S baseline (BL) score, treatment and HAMD total BL score. The last non-missing OT score prior to TIME was carried forward to estimate missing data points for remaining study visits of the treatment period. BL value was defined as the last non-missing value at or prior to the randomization. Change from BL was calculated by subtracting BL from the specific post-BL value. If BL or post-BL value was missing, the change from BL was set to missing. | Baseline and up to 36 weeks |
| Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | YMRS consists of 11 items: Elevated Mood, Increased Motor Activity/Energy, Sexual Interest, Sleep, Irritability, Speech, Language/Thought Disorder, Content, Disruptive/Aggressive Behaviour, Appearance, and Insight. Investigators rated par. from 0 to 4 (or 8) for each of these items. Total score is the sum of all subscales, from 0 to 60 (higher is worse). Data was collected on Wks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32, 36. Analysis was performed using ANCOVA with covariates of site, CGI-S BL score, treatment and YMRS total BL score. In LOCF datasets, the last non-missing OT score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. BL value was defined as the last non-missing values at or prior to the randomization. Change from BL at the time point of interest was calculated by subtracting BL value from the individual post-BL value. If either the BL or post-BL value was missing, change from BL was set to missing. | Baseline and up to 36 weeks |
| Change From Baseline of Global Assessment Scale (GAS) Total Score | For GAS, investigators rated par. for lowest level of functioning during the previous week. The scale has a 10 score categories: 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, 91-100, using intermediary levels when appropriate (from 100 to 1, Lower is worse.). Data was collected on Weeks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32, 36. Analysis was performed using ANCOVA with covariates of site, CGI-S BL score, treatment and GAS total BL score. In presented LOCF datasets, the last non-missing on therapy score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. The BL value was defined as the last non-missing values at or prior to the randomization. The change from BL at the time point of interest was calculated by subtracting the BL values from the individual post-BL values. If either the BL or post-BL value was missing, the change from BL was set to missing as well. | Baseline and up to 36 weeks |
| Change From Baseline in Body Weight | Participant's body weight was measured on Weeks 0, 4, 8, 12, 16, 20, 24, 32 and 36. Analysis was performed using ANCOVA with covariates of site, CGI-S baseline score, treatment and baseline body weight. In presented LOCF datasets, the last non-missing on therapy score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. The baseline value was defined as the last non-missing values at or prior to the randomization. The change from baseline at the time point of interest was calculated by subtracting the baseline values from the individual post-baseline values. If either the baseline or post-baseline value was missing, the change from baseline was set to missing as well. | Baseline and up to 36 weeks. |
| Guangzhou |
| Guangdong |
| 510370 |
| China |
| GSK Investigational Site | Guangzhou | Guangdong | 510630 | China |
| GSK Investigational Site | Baoding | Hebei | 071000 | China |
| GSK Investigational Site | Shijiazhuang | Hebei | 050000 | China |
| GSK Investigational Site | Harbin | Heilongjiang | 150070 | China |
| GSK Investigational Site | Changshacun | Henan | 410011 | China |
| GSK Investigational Site | Xinxiang | Henan | China |
| GSK Investigational Site | Wuhan | Hubei | 430022 | China |
| GSK Investigational Site | Changsha | Hunan | China |
| GSK Investigational Site | Nanjing | Jiangsu | 210029 | China |
| GSK Investigational Site | Xi'an | Shaanxi | 710032 | China |
| GSK Investigational Site | Taiyuan | Shanxi | China |
| GSK Investigational Site | Chengdu | Sichuan | 610041 | China |
| GSK Investigational Site | Kunming | Yunnan | 650032 | China |
| GSK Investigational Site | Hangzhou | Zhejiang | 310003 | China |
| GSK Investigational Site | Hangzhou | Zhejiang | 310009 | China |
| GSK Investigational Site | Beijing | 100083 | China |
| GSK Investigational Site | Beijing | 100088 | China |
| GSK Investigational Site | Beijing | 100096 | China |
| GSK Investigational Site | Shanghai | 200030 | China |
| Protocol Violation |
|
| Met protocol-defined stopping criteria |
|
| Lost to Follow-up |
|
| Physician Decision |
|
| Withdrawal by Subject |
|
| NOT COMPLETED |
|
|
| Mean |
| Standard Deviation |
| Years |
|
| Gender | Data is presented for Open Label Phase. | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Data is presented for Open Label Phase. | Number | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Randomized Placebo | Participants who reached a stable dose of lamotrigine and met response criteria, defined as a Clinical Global Impression of Severity (CGI-S) score <= 3 maintained for at least 4 continuous weeks and lamotrigine 200 mg/day monotherapy maintained for at least 1 week during open label phase, were enrolled in the double-blind phase of the study. Participants received placebo for 36 weeks. |
| OG001 | Randomized Lamotrigine 200 mg/Day | Participants who reached a stable dose of lamotrigine and met response criteria, defined as a CGI-S score <= 3 maintained for at least 4 continuous weeks and lamotrigine 200 mg/day monotherapy maintained for at least 1 week during open label phase, were enrolled in the double-blind phase of the study. Participants received lamotrigine 200 mg/day for 36 weeks. |
|
|
|
| Secondary | Time to Intervention for Manic, Hypomanic or Mixed Episode (TIMan) | TIMan was analyzed using using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. Par. prematurely discontinued from the study prior to reaching the event were censored at the time of discontinuation. | RD Full Analysis Population."NA" implies no data are available. Only those par. with available data at indicated time points were analyzed. | Posted | Median | 95% Confidence Interval | Days | 36 weeks |
|
|
|
|
| Secondary | Time to Intervention for Depressive Episode (TIDep) | TIDep was analyzed using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. Par. prematurely discontinued from the study prior to reaching the event were censored at the time of discontinuation. | RD Full Analysis Population. "NA" implies no data are available. Only those par. with available data at indicated time points were analyzed. | Posted | Median | 95% Confidence Interval | Days | 36 weeks |
|
|
|
|
| Secondary | Overall Survival in Study (TIME-SIS). | TIME-SIS was defined as the time to intervention (addition of pharmacotherapy or ECT) for any mood episode, or to the time when the participant is withdrawn for any reason after randomization. The premature discontinuation of a participant prior to reaching TIME, for any reason, was treated as an event related to bipolar disorder. All participants prematurely discontinued prior to the TIME event in this analysis were to be assumed to have reached TIME. TIMS-SIS was analyzed using Cox proportional hazards regression model with covariates of site, CGI-S baseline score, treatment and treatment by CGI-S baseline score interaction. The overall hazard ratio for treatment group could not be calculated due to different CGI-S baseline score level. Par. prematurely discontinued from the study prior to reaching the event were censored at the time of discontinuation. | RD Full Analysis Population. "NA" implies no data are available. Only those par. with available data at indicated time points were analyzed. | Posted | Median | 95% Confidence Interval | Days | 36 weeks |
|
|
|
|
| Secondary | Change From Baseline in Clinical Global Impression of Improvements (CGI-I) | The CGI-I is a 7-point scale where investigator were asked to assess the participant's illness at the time of assessment (improved or worsened) relative to a baseline state. In this scale, 1= very much improved; 2= much improved; 3= minimally improved; 4= no change; 5= minimally worse; 6= much worse; or 7= very much worse. Analysis was performed using Analysis of covariance with covariates of site, CGI-S baseline score and treatment. In presented Last-observation-carried-forward datasets, the last non-missing on therapy (OT) score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. Baseline value was defined as the last non-missing values at or prior to the randomization. Change from baseline at the time point of interest was calculated by subtracting the baseline values from the individual post-baseline values. If either baseline or post-baseline value was missing, the change from baseline was set to missing. | RD Full Analysis Population. | Posted | Least Squares Mean | Standard Error | Score on a scale | Baseline and up to 36 weeks |
|
|
|
|
| Secondary | Change From Baseline in Clinical Global Impression of Severity (CGI-S) | The CGI-S is a 7-point scale where investigator were asked to rate the severity of the participant's illness at the time of assessment on severity of mental illness, where 1= normal, and 7= extremely ill. Data was collected on Weeks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32 and 36. Analysis performed using Analysis of Covariance (ANCOVA) with covariates of site, CGI-S baseline score (Open label phase), treatment and CGI-S baseline score. In presented Last observation carried forward (LOCF) datasets, last non-missing on therapy score prior to TIME was carried forward to estimate missing data points for remaining study visits of treatment period. The baseline value was defined as last non-missing values at or prior to the randomization. The change from baseline at the time point of interest was calculated by subtracting the baseline values from individual post-baseline values. If either the baseline or post-baseline value was missing, the change from baseline was set to missing as well. | RD Full Analysis Population. | Posted | Least Squares Mean | Standard Error | Score on a scale | Baseline and up to 36 weeks |
|
|
|
|
| Secondary | Change From Baseline in Hamilton Depression Rating Scale (HAMD) | HAMD consists of 17 items: depressed mood, feelings of guilt, suicide, insomnia-early, middle, late, work and activities, retardation, agitation, anxiety psychic, anxiety somatic, somatic symptoms gastro-intestinal, general somatic symptoms, hypochondriasis, loss of weight, and insight. Investigators rated par. from 0 to 4 (or 2) for these items. Total score is sum of all subscales (0 to 52, higher is worse). Data was collected on Wks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32, 36. Analysis was performed using ANCOVA with covariates of site, CGI-S baseline (BL) score, treatment and HAMD total BL score. The last non-missing OT score prior to TIME was carried forward to estimate missing data points for remaining study visits of the treatment period. BL value was defined as the last non-missing value at or prior to the randomization. Change from BL was calculated by subtracting BL from the specific post-BL value. If BL or post-BL value was missing, the change from BL was set to missing. | RD Full Analysis Population | Posted | Least Squares Mean | Standard Error | Score on a scale | Baseline and up to 36 weeks |
|
|
|
|
| Secondary | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | YMRS consists of 11 items: Elevated Mood, Increased Motor Activity/Energy, Sexual Interest, Sleep, Irritability, Speech, Language/Thought Disorder, Content, Disruptive/Aggressive Behaviour, Appearance, and Insight. Investigators rated par. from 0 to 4 (or 8) for each of these items. Total score is the sum of all subscales, from 0 to 60 (higher is worse). Data was collected on Wks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32, 36. Analysis was performed using ANCOVA with covariates of site, CGI-S BL score, treatment and YMRS total BL score. In LOCF datasets, the last non-missing OT score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. BL value was defined as the last non-missing values at or prior to the randomization. Change from BL at the time point of interest was calculated by subtracting BL value from the individual post-BL value. If either the BL or post-BL value was missing, change from BL was set to missing. | RD Full Analysis Population | Posted | Least Squares Mean | Standard Error | Score on a scale | Baseline and up to 36 weeks |
|
|
|
|
| Secondary | Change From Baseline of Global Assessment Scale (GAS) Total Score | For GAS, investigators rated par. for lowest level of functioning during the previous week. The scale has a 10 score categories: 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, 91-100, using intermediary levels when appropriate (from 100 to 1, Lower is worse.). Data was collected on Weeks 0, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32, 36. Analysis was performed using ANCOVA with covariates of site, CGI-S BL score, treatment and GAS total BL score. In presented LOCF datasets, the last non-missing on therapy score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. The BL value was defined as the last non-missing values at or prior to the randomization. The change from BL at the time point of interest was calculated by subtracting the BL values from the individual post-BL values. If either the BL or post-BL value was missing, the change from BL was set to missing as well. | RD Full Analysis Population | Posted | Least Squares Mean | Standard Error | Score on a scale | Baseline and up to 36 weeks |
|
|
|
|
| Secondary | Change From Baseline in Body Weight | Participant's body weight was measured on Weeks 0, 4, 8, 12, 16, 20, 24, 32 and 36. Analysis was performed using ANCOVA with covariates of site, CGI-S baseline score, treatment and baseline body weight. In presented LOCF datasets, the last non-missing on therapy score prior to TIME was carried forward to estimate missing data points for the remaining study visits of the treatment period. The baseline value was defined as the last non-missing values at or prior to the randomization. The change from baseline at the time point of interest was calculated by subtracting the baseline values from the individual post-baseline values. If either the baseline or post-baseline value was missing, the change from baseline was set to missing as well. | RD Full Analysis Population. Only those par. with available data at indicated time points were analyzed. | Posted | Least Squares Mean | Standard Error | Kilograms | Baseline and up to 36 weeks. |
|
|
|
|
| 3 |
| 133 |
| 46 |
| 133 |
| EG001 | Randomized Lamotrigine 200 mg/Day | Participants who reached a stable dose of lamotrigine and met response criteria, defined as a CGI-S score <= 3 maintained for at least 4 continuous weeks and lamotrigine 200 mg/day monotherapy maintained for at least 1 week during open label phase, were enrolled in the double-blind phase of the study. Participants received lamotrigine 200 mg/day for 36 weeks. | 2 | 131 | 40 | 131 |
| Suicide attempt | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Concussion | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Laceration | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Brain stem infarction | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Herpes zoster | Infections and infestations | MedDRA | Systematic Assessment |
|
| Pericoronitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood glucose increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood pressure increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood triglycerides increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood uric acid increased | Investigations | MedDRA | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA | Systematic Assessment |
|
| Weight increased | Investigations | MedDRA | Systematic Assessment |
|
| Bilirubin conjugated increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood phosphorus increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood urine present | Investigations | MedDRA | Systematic Assessment |
|
| Electrocardiogram ST segment abnormal | Investigations | MedDRA | Systematic Assessment |
|
| Electrocardiogram T wave abnormal | Investigations | MedDRA | Systematic Assessment |
|
| Electrocardiogram abnormal | Investigations | MedDRA | Systematic Assessment |
|
| Heart rate decreased | Investigations | MedDRA | Systematic Assessment |
|
| Heart rate increased | Investigations | MedDRA | Systematic Assessment |
|
| Neutrophil count increased | Investigations | MedDRA | Systematic Assessment |
|
| Specific gravity urine increased | Investigations | MedDRA | Systematic Assessment |
|
| Urine ketone body present | Investigations | MedDRA | Systematic Assessment |
|
| White blood cell count increased | Investigations | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Chronic gastritis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Colitis ulcerative | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Lip ulceration | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Retching | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Poor quality sleep | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Depressed mood | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Affect lability | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Emotional distress | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Hyposomnia | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Initial insomnia | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Irritability | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Listless | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Sleep disorder | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Suicidal ideation | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA | Systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA | Systematic Assessment |
|
| Malaise | General disorders | MedDRA | Systematic Assessment |
|
| Pain | General disorders | MedDRA | Systematic Assessment |
|
| Thirst | General disorders | MedDRA | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Skin mass | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Swelling face | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Bundle branch block right | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Myocardial infarction | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Myocardial ischaemia | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Palpitations | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Gout | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hepatic function abnormal | Hepatobiliary disorders | MedDRA | Systematic Assessment |
|
| Cholecystitis | Hepatobiliary disorders | MedDRA | Systematic Assessment |
|
| Granulocytopenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Dry eye | Eye disorders | MedDRA | Systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA | Systematic Assessment |
|
| Nephrolithiasis | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| Thyroid disorder | Endocrine disorders | MedDRA | Systematic Assessment |
|
| Food allergy | Immune system disorders | MedDRA | Systematic Assessment |
|
| Menstrual disorder | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
| =0.061 |
| Adjusted Hazard Ratio |
| 0.95 |
| 2-Sided |
| 95 |
| 0.55 |
| 1.66 |
p value with Site as covariate |
| No |
| Superiority or Other |
| Regression, Cox | =0.505 | Adjusted Hazard Ratio | 0.95 | 2-Sided | 95 | 0.55 | 1.66 | p value with CGI-S Baseline Score as covariate | No | Superiority or Other |
| =0.955 |
| Adjusted Hazard Ratio |
| 0.79 |
| 2-Sided |
| 95 |
| 0.48 |
| 1.32 |
p value with Site as covariate |
| No |
| Superiority or Other |
| Regression, Cox | =0.874 | Adjusted Hazard Ratio | 0.79 | 2-Sided | 95 | 0.48 | 1.32 | p value with CGI-S Baseline Score as covariate | No | Superiority or Other |
| =0.036 |
| Adjusted Hazard Ratio |
| 1.02 |
| 2-Sided |
| 95 |
| 0.73 |
| 1.40 |
p value with Site as covariate |
| No |
| Superiority or Other |
| Regression, Cox | =0.509 | Adjusted Hazard Ratio | 1.02 | 2-Sided | 95 | 0.73 | 1.40 | p value with CGI-S Baseline Score as covariate | No | Superiority or Other |