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Lamotrigine Phase III Study in Bipolar I Disorder

29 de noviembre de 2016 actualizado por: GlaxoSmithKline

A Fixed-Dose Study of Lamotrigine Versus Placebo in the Long Term Prevention of Relapse and/or Recurrence of a Manic, Hypomanic, Mixed or Depressive Episode in Adult Subjects With Bipolar I Disorder

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 Subjects who have not met response criteria after 16 weeks of participation in the open-label phase will be withdrawn from the study.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.

Descripción general del estudio

Estado

Terminado

Condiciones

Intervención / Tratamiento

Tipo de estudio

Intervencionista

Inscripción (Actual)

265

Fase

  • Fase 3

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

  • Porcelana
      • Beijing, Porcelana, 100083
        • GSK Investigational Site
      • Beijing, Porcelana, 100088
        • GSK Investigational Site
      • Beijing, Porcelana, 100096
        • GSK Investigational Site
      • Shanghai, Porcelana, 200030
        • GSK Investigational Site
    • Guangdong
      • Guangzhou, Guangdong, Porcelana, 510180
        • GSK Investigational Site
      • Guangzhou, Guangdong, Porcelana, 510370
        • GSK Investigational Site
      • Guangzhou, Guangdong, Porcelana, 510630
        • GSK Investigational Site
    • Hebei
      • Baoding, Hebei, Porcelana, 071000
        • GSK Investigational Site
      • Shijiazhuang, Hebei, Porcelana, 050000
        • GSK Investigational Site
    • Heilongjiang
      • Harbin, Heilongjiang, Porcelana, 150070
        • GSK Investigational Site
    • Henan
      • Changsha, Henan, Porcelana, 410011
        • GSK Investigational Site
      • Xinxiang, Henan, Porcelana
        • GSK Investigational Site
    • Hubei
      • Wuhan, Hubei, Porcelana, 430022
        • GSK Investigational Site
    • Hunan
      • Changsha, Hunan, Porcelana
        • GSK Investigational Site
    • Jiangsu
      • Nanjing, Jiangsu, Porcelana, 210029
        • GSK Investigational Site
    • Shaanxi
      • Xi'an, Shaanxi, Porcelana, 710032
        • GSK Investigational Site
    • Shanxi
      • Taiyuan, Shanxi, Porcelana
        • GSK Investigational Site
    • Sichuan
      • Chengdu, Sichuan, Porcelana, 610041
        • GSK Investigational Site
    • Yunnan
      • Kunming, Yunnan, Porcelana, 650032
        • GSK Investigational Site
    • Zhejiang
      • Hangzhou, Zhejiang, Porcelana, 310009
        • GSK Investigational Site
      • Hangzhou, Zhejiang, Porcelana, 310003
        • GSK Investigational Site

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

18 años y mayores (Adulto, Adulto Mayor)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Todos

Descripción

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

  • Has been on Lamotrigine 200 mg/day monotherapy for at least 1 week.
  • CGI-S score <= 3 for at least 4 continuous weeks of treatment prior to randomization.
  • Has demonstrated adequate compliance with IP (compliance rate: 75%-125%, inclusive).

Exclusion Criteria:

For open label

  • Has met Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for rapid cycling and has had more than 4 manic, hypomanic, mixed or depressive episodes in the 12-month period prior to enrollment.
  • Has a significant DSM-IV Axis II diagnosis which would suggest non-responsiveness to pharmacotherapy for bipolar disorder or non-compliance with the protocol.
  • Has a current or previous diagnosis of an Axis I disorder (including anorexia nervosa or bulimia nervosa) with the exception of bipolar disorder or has received corresponding treatment, or has been diagnosed with dysthymia within the previous 2 years.
  • Has signs or symptoms of psychosis.
  • The subject, in the investigator's judgment, poses a suicidal risk, has attempted suicide within 6 months prior to screening (assessed using the Columbia Suicide Severity Rating Scale Baseline) or .
  • Has documented Intelligence quotient < 70 or suspected mental retardation.
  • Has a history of substance abuse or dependence within 12 months prior to enrolment (DSM-IV defined substance categories, excluding nicotine and caffeine and including alcohol), or has as a positive urine test for illicit drug use (excluding nicotine and caffeine).
  • Has received fluoxetine within 4 weeks prior to entry into the open-label phase; has received oral contraceptives or other hormonal preparations containing estrogen within 2 weeks prior to entry into the open-label phase; has received lopinavir/ritonavir or atazanavir /ritonavir within 7 days prior to the baseline visit.
  • Has a clinically significant and/or unstable medical disorder (with or without lab test results); or clinically significant test results (thyroid function, electrocardiogram, hematology, clinical chemistry, or urinalysis) as per investigator's judgment; or a disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of lamotrigine; per investigator's clinical judgment (after consulting GSK medical monitor), might pose a safety concern; or interfere with the accurate assessment of safety or efficacy.
  • Has a history or current diagnosis of epilepsy.
  • Is morbidly obese, i.e. if Body Mass Index (BMI) is > 35 {BMI = Body weight (in kg) divided by (Height in meters squared).
  • Single or average QT interval corrected by Bazette's formulaQTcB or QTc > 450 millisecond (msec); for patients with bundle branch block QTc > 480 msec.
  • Has a history of hepatic dysfunction; Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) >= 2 x upper limit of normal (ULN); Alkaline phosphatase (ALP) or total bilirubin > 1.5 x ULN (excluding total bilirubin > 1.5 x ULN but direct bilirubin < 35%) or other conditions which, in the investigator's judgment, would render patients unsuitable for the study.
  • Has a history of drug allergy (including rash) or a medically significant adverse effect from any ingredient of lamotrigine, or a history of rash due to anti-epileptic drugs or has frequent and/or serious hypersensitivity reaction to multiple drugs.
  • Participation in any study related to lamotrigine within 6 months before screening or has received lamotrigine within 4 weeks before screening.
  • Participation in another clinical study unrelated to the current illness currently or within the previous 30 days, or 3 months for studies related to the current illness.
  • Initiation of systematic psychotherapy within 3 months prior to screening or planned initiation of systematic psychotherapy during the study.
  • Female subjects who are pregnant, lactating or do not agree to use the contraceptive methods such as use of condom, injection of progesterone, a reliable barrier method of birth control, partner with vasectomy or abstinence during the study.

For randomized double blind phase

  • Has signs or symptoms of psychosis.
  • Requires treatment for a manic or mixed episode in the open-label phase with new courses of lithium, psychotropic drugs or other drugs with a half-life greater than 14 days.
  • Has become actively suicidal and/or has a score >=3 on item 3 of the HAMD.
  • Has tested positive for an illicit drug on lab analysis administered before randomization or alcohol abuse/addiction.
  • Has had a change in lamotrigine dosage during the last week of the open-label phase.

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: Aleatorizado
  • Modelo Intervencionista: Asignación paralela
  • Enmascaramiento: Doble

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Comparador de placebos: Placebo
Droga: Placebo
Placebo
Experimental: Lamotrigine CD
lamotrigine chewable dispersible tablets 25mg, 50mg, 100mg
Droga: Lamotrigine
in the double blind phase, lamotrigine 200mg/day will be used among half of eligible subjects after randomization

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Time to Intervention for Any Mood Episode (TIME)
Periodo de tiempo: 36 weeks (wks)
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)

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Time to Intervention for Manic, Hypomanic or Mixed Episode (TIMan)
Periodo de tiempo: 36 weeks
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.
36 weeks
Time to Intervention for Depressive Episode (TIDep)
Periodo de tiempo: 36 weeks
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).
Periodo de tiempo: 36 weeks
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)
Periodo de tiempo: Baseline and up to 36 weeks
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)
Periodo de tiempo: Baseline and up to 36 weeks
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)
Periodo de tiempo: Baseline and up to 36 weeks
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
Periodo de tiempo: Baseline and up to 36 weeks
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
Periodo de tiempo: Baseline and up to 36 weeks
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
Periodo de tiempo: Baseline and up to 36 weeks.
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.

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

GlaxoSmithKline

Publicaciones y enlaces útiles

La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.

Publicaciones Generales

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de agosto de 2012

Finalización primaria (Actual)

1 de diciembre de 2015

Finalización del estudio (Actual)

1 de diciembre de 2015

Fechas de registro del estudio

Enviado por primera vez

17 de mayo de 2012

Primero enviado que cumplió con los criterios de control de calidad

17 de mayo de 2012

Publicado por primera vez (Estimar)

21 de mayo de 2012

Actualizaciones de registros de estudio

Última actualización publicada (Estimar)

23 de enero de 2017

Última actualización enviada que cumplió con los criterios de control de calidad

29 de noviembre de 2016

Última verificación

1 de septiembre de 2016

Más información

Términos relacionados con este estudio

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • 113783

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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