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Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study

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ClinicalTrials.gov Identifier: NCT02100644
Recruitment Status : Completed
First Posted : April 1, 2014
Results First Posted : February 1, 2016
Last Update Posted : November 17, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this study is to examine whether the VPA (Valproate) dose can be reduced by additional administration of LTG (Lamotrigine) in Japanese pre-menopausal female epilepsy patients aged 15 years or older, whose seizures are well controlled by VPA monotherapy.

Condition or disease Intervention/treatment Phase
Epilepsy Drug: Lamotrigine tablets 25/100 mg Phase 4

Detailed Description:

RATIONALE In several studies that investigated the effects of in utero exposure to AEDs (antiepileptic drugs) on fetal malformations and intellectual development in children after birth, it has been reported that VPA causes neonatal malformations and decreases intelligence of children in a dose dependent manner, whereas such a risk is low in LTG (Hernandez-Díaz et al., 2012; Meador et al., 2013). It has also been reported that LTG as adjunctive therapy with VPA is effective in inhibiting seizures in patients with poorly controlled seizures, and adverse events under VPA monotherapy can be relieved by subsequently reducing VPA dose after LTG is combined (Sale et al., 2005; Jozwiak et al., 2000; Morris et al, 2004; Buchanan, 1996). Thus, by considering the benefits of replacing VPA by LTG in childbearing women, we will examine whether VPA dose can be reduced by introducing LTG in Japanese female epilepsy patients under VPA monotherapy (aged ≥ 15 years, pre-menopausal).

STUDY DESIGN Single arm, multicenter, and open-label study TIME FRAME

  • Screening(Retrospective review of medical records for 12 weeks)
  • LTG escalation phase (8-18 weeks)
  • VPA reduction phase (3-16 weeks)
  • LTG & VPA maintenance phase (12 weeks)
  • Follow up (1-4 weeks) PRIMARY OBJECTIVE To examine whether the VPA dose can be reduced by additional administration of LTG (up to 200 mg/d if there are no safety concerns) in Japanese pre-menopausal female epilepsy patients aged 15 years or older, whose seizures are well controlled by VPA monotherapy (fixed maintenance dose of 400-1200 mg/d).

SECONDARY OBJECTIVES

  • To investigate the steady state concentration of LTG immediately before VPA dose reduction, at the time of VPA dose reduction, and during the LTG&VPA maintenance phase.
  • To investigate the safety and tolerability associated with additional administration of LTG followed by dose reduction of VPA.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study -
Actual Study Start Date : April 12, 2014
Actual Primary Completion Date : May 11, 2015
Actual Study Completion Date : May 11, 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Epilepsy
Drug Information available for: Lamotrigine

Arm Intervention/treatment
Experimental: Lamotrigine
The study objective is to examine whether the VPA dose can be reduced by additional administration of LTG in Japanese pre-menopausal female epilepsy patients, whose seizures are well controlled by VPA monotherapy. Then VPA is the standard product in this stuudy, not the investigational product.
Drug: Lamotrigine tablets 25/100 mg
Lamotrigine (LTG) is administered according to the package insert: that is, 25 mg of LTG will be orally administered once every other day for the first 2 weeks and then once daily for the next 2 weeks. Thereafter, the dose will be gradually escalated by 25-50 mg every 1-2 week for once or twice daily administration. During the VPA reduction phase and LTG&VPA maintenance phase, as specified in the information of package insert, maintenance dose of LTG will be administered twice daily.




Primary Outcome Measures :
  1. Percentage of Participants Who Achieved Reduction in Daily VPA Dose [ Time Frame: Baseline and at the end of the LTG and VPA Maintenance Phase, 24-46 weeks that can be varied by durations of the LTG Escalation Phase and VPA Reduction Phase ]
    The VPA dose reduction from Baseline is defined as post VPA dose minus the Baseline VPA dose < 0. Baseline VPA dose is the dose at the Baseline visit (Week 0) and the post VPA dose is the last VPA dose during the LTG and VPA Maintenance Phase. Percentage of participants with dose reduction during the LTG and VPA Maintenance Phase is presented.

  2. Percent Change in the VPA Dose [ Time Frame: Baseline and at the end of the LTG and VPA Maintenance Phase, 24-46 weeks that can be varied by durations of the LTG Escalation Phase and VPA Reduction Phase ]
    Percent change in VPA dose is calculated as (pre-dose - post-dose) / pre-dose x 100. Pre-dose is the VPA dose at the Baseline visit and post-dose is the last VPA dose during the LTG and VPA Maintenance Phase.


Secondary Outcome Measures :
  1. Number of Days in Total That Epileptic Seizures Occurred up to the LTG and VPA Maintenance Phase [ Time Frame: Baseline and up to 46 weeks ]
    The participants with no seizure, had no record in seizure dairy. Only those participants with more than one seizure were assessed for this Outcome Measure.

  2. Change From Baseline in Quality of Life in Epilepsy-31-P (QOLIE-31-P) in Participants Aged 18 Years and Older [ Time Frame: Baseline and up to 46 weeks ]
    QOLIE-31-P is a questionnaire analyzed according to the scoring manual at Baseline, at the end of LTG/VPA Maintenance Phase and withdrawals for the participants aged 18 years and older (n=26, excluding 1 participant withdrawn due to protocol violation). Overall score was calculated as an average of sub scores that were normalized to 0 to 100. QOLIE-31-P has 7 subscale items (energy, mood, daily activities, cognition, medication effect, seizure worry and overall QOL). Higher score presents higher quality of life. Epileptic symptoms generally affect the QOL of participants, and so QOLIE-31-P is world widely used for the QOL assessment of adult participants. Baseline is defined as Day 1 (pre-dose) value. Change from Baseline is calculated as post-dose visit value minus Baseline value.

  3. Change From Baseline in Quality of Life in Epilepsy for Adolescents (QOLIE-AD-48) in Participants Aged 15-17 Years [ Time Frame: Baseline and up to 46 weeks ]
    QOLIE-AD-48 is a questionnaire analyzed according to the scoring manual at Baseline, at the end of the LTG/VPA Maintenance Phase and withdrawals for participants aged 15-17 years (n=6). Particpants who has started by QOLIE-AD-48 were using the same questionnaire even after 18 years old. Overall score was calculated as an average of sub scores that were normalized to 0 to 100. QOLIE-AD-48 has 8 subscale items (epilepsy impact, memory/concentration, physical fuctioning, stigma, social support, school behavior, attitudes towards epilepsy and health perceptions). Higher score presents higher quality of life. Epileptic symptoms generally affect the QOL of participants, and so QOLIE-AD-48 is world widely used for the QOL assessment of non-adult participants. Baseline is defined as Day 1 (pre-dose) value. Change from Baseline is calculated as post-dose visit value minus Baseline value.

  4. Percentage of Participants Who Completed or Discontinued From the Study [ Time Frame: Up to 50 weeks ]
    Following cases were considered for participants to have completed a part of or whole of the study. For whole period completion: participants who completed the last LTG and VPA Maintenance Phase visit (M5) in the LTG and VPA Maintenance Phase and follow-up examination. For LTG Escalation Phase completion: participants who reached 200 mg/d of LTG (or 100-200 mg/d of LTG if there were safety concerns) within 8-18 weeks of the phase. For VPA Reduction Phase completion: participants who completed the last fixed dose of VPA Reduction Phase visit (0 mg/d) (FR4) of the phase. For LTG and VPA Maintenance Phase completion: participants who completed M5 of the phase. Participants who met any of the withdrawal criteria after the start of investigational product were considered to have discontinued the study. Percentage of participants who completed or discontinued/withdrawn from the study is presented.

  5. Number of Participants With Adverse Events (AEs), AEs Leading to Discontinuation of the Investigational Product and/or Withdrawal From the Study, Drug-related AEs, Deaths and Serious Adverse Events (SAEs) Throughout the Study [ Time Frame: From the start of study treatment until follow-up (up to 50 weeks) ]
    An AE is defined as untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity, is a congenital anomaly/birth defect, based on medical or scientific judgement and all events of possible drug-induced liver injury.



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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. (Target disease) Epilepsy patients having the following seizure types as classified by the International Classification of Epileptic Seizures

    • Partial seizures (with or without secondary generalization)
    • Tonic-clonic seizures with or without myoclonus but without other generalized seizure type(s)
  2. Subjects having a confident diagnosis of epilepsy that is uncomplicated by pseudoseizures such as psychogenic nonepileptic seizures
  3. Subjects whose seizures have been controlled for 12 weeks prior to start of the investigational product with a stable maintenance dose of VPA monotherapy (400-1200 mg/d)
  4. (Age and gender)

Japanese pre-menopausal women who are at least 15 years old at the time of consent, not lactating, and can agree to use any of the following types of contraception in a reliable fashion:

  1. Complete abstinence during the study as well as for a period after the study to account for elimination of the investigational product (a minimum of 2 weeks)
  2. Consistent and correct use of any of the following contraceptive methods

    • Surgical sterilization of male partner (i.e., male partner is the sole sexual partner for the female subject and is sterilized prior to the subject's entry into the study)
    • Intrauterine device with a failure rate of less than 1% per year
    • Double barrier method (e.g., spermicide plus a condom or a diaphragm) Note: Women who have had a hysterectomy or tubal ligation are considered to be of non-childbearing potential. Since a pharmacokinetic interaction has been observed between LTG and estrogen-based oral contraceptives, the use of hormonal therapy such as for contraception or hormone replacement therapy is not allowed.

      5.Outpatients 6.Subjects who can keep a seizure diary 7.Subjects who can understand and sign the informed consent. If the subject is under 20 years old at the time of consent, both the subject and subject's legally acceptable representative have to sign the consent to participate in the study.

      8.QTc <480 msec for subjects with bundle branch block or QTc <450 msec for other subjects, in which QTc is measured by either single or triplicate-averaged ECG 9.Subjects who can comply with dosing of the investigational and standard products and all study procedures

Exclusion Criteria:

  1. Subjects with a history of hypersensitivity to LTG
  2. Subjects with a history of rash associated with other AED treatments.
  3. Subjects who have received another AED besides VPA during the 12 weeks prior to start of the investigational product
  4. Subjects with status epilepticus during the 6 months prior to start of the investigational product
  5. Subjects with a history of substance (including alcohol and drug) dependence or substance abuse as defined by the DSM-IV-TR within 12 months or 1 month, respectively, prior to start of the investigational product
  6. Subjects with a severe acute or chronic illness likely to impair drug absorption, distribution, metabolism, or excretion; or subjects with any unstable physical symptom likely to require hospitalization during the study
  7. Subjects with a severe psychiatric disorder that affects the procedures of the study or drug assessment
  8. Subjects with an acute or progressive neurological disorder or an organic disease
  9. Subjects with any clinically significant cardiac, renal, or hepatic medical condition. Any patient with these conditions will be excluded from the study even if these conditions are being controlled with a chronic therapy.
  10. Subjects with an unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Note: Chronic stable hepatitis B and C are acceptable if the subjects otherwise meet the inclusion criteria. However, the subjects with chronic stable hepatitis B will be excluded if significant immunosuppressive agents are being administered due to a risk of hepatitis B reactivation.
  11. Subjects who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study
  12. Subjects who are suspected to have an urea cycle disorder as below:

    • Subjects with a history of encephalopathy or coma of unknown cause
    • Subjects with a family history of infant death of unknown cause or urea cycle disorder
  13. Subjects taking inducers of LTG glucuronidation (i.e., rifampicinor lopinavir/ritonavir), atazanavir/ritonavir, risperidone, or oral contraceptives or hormone drugs containing estrogen
  14. Subjects taking carbapenem antibiotic (i.e., panipenem/betamipron, meropenem hydrate, imipenem hydrate/cilastatin sodium, biapenem, doripenem hydrate, or tebipenem pivoxil)
  15. Subjects who have participated in other clinical studies within 3 months prior to start of the investigational product
  16. Subjects who have had active suicidal plans/intent or suicidal thoughts in the past 3 months prior to start of the investigational product; or subjects who have history of suicide attempts in the last 1 year prior to start of the investigational product or of multiple suicide attempts in their lifetime
  17. Subjects whom the investigator or subinvestigator considers ineligible for the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02100644


Locations
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Japan
GSK Investigational Site
Hyogo, Japan, 664-8540
GSK Investigational Site
Kagoshima, Japan, 892-0844
GSK Investigational Site
Kyoto, Japan, 606-8507
GSK Investigational Site
Osaka, Japan, 560-8565
GSK Investigational Site
Saitama, Japan, 351-8551
GSK Investigational Site
Shizuoka, Japan, 430-8558
GSK Investigational Site
Tokyo, Japan, 185-0012
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

Additional Information:
Study Data/Documents: Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 200776
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 200776
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 200776
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 200776
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 200776
For additional information about this study please refer to the GSK Clinical Study Register

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02100644     History of Changes
Other Study ID Numbers: 200776
First Posted: April 1, 2014    Key Record Dates
Results First Posted: February 1, 2016
Last Update Posted: November 17, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Additional relevant MeSH terms:
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Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lamotrigine
Valproic Acid
Anticonvulsants
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Sodium Channel Blockers
Enzyme Inhibitors
GABA Agents
Neurotransmitter Agents
Antimanic Agents