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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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 -

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: Lamotrigine tablets 25/100 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (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) Subjects having a confident diagnosis of epilepsy that is uncomplicated by pseudoseizures such as psychogenic nonepileptic seizures 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) (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: 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) 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: Subjects with a history of hypersensitivity to LTG Subjects with a history of rash associated with other AED treatments. Subjects who have received another AED besides VPA during the 12 weeks prior to start of the investigational product Subjects with status epilepticus during the 6 months prior to start of the investigational product 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 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 Subjects with a severe psychiatric disorder that affects the procedures of the study or drug assessment Subjects with an acute or progressive neurological disorder or an organic disease 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. 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. Subjects who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study 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 Subjects taking inducers of LTG glucuronidation (i.e., rifampicinor lopinavir/ritonavir), atazanavir/ritonavir, risperidone, or oral contraceptives or hormone drugs containing estrogen Subjects taking carbapenem antibiotic (i.e., panipenem/betamipron, meropenem hydrate, imipenem hydrate/cilastatin sodium, biapenem, doripenem hydrate, or tebipenem pivoxil) Subjects who have participated in other clinical studies within 3 months prior to start of the investigational product 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 Subjects whom the investigator or subinvestigator considers ineligible for the study

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lamotrigine<br>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<br>* 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&amp;VPA maintenance phase, as specified in the information of package insert, maintenance dose of LTG will be administered twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Reduction in Daily VPA Dose | 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. | 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 the VPA Dose | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days in Total That Epileptic Seizures Occurred up to the LTG and VPA Maintenance Phase | 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. | Baseline and up to 46 weeks | 
| Change From Baseline in Quality of Life in Epilepsy-31-P (QOLIE-31-P) in Participants Aged 18 Years and Older | 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. | Baseline and up to 46 weeks | 
| Change From Baseline in Quality of Life in Epilepsy for Adolescents (QOLIE-AD-48) in Participants Aged 15-17 Years | 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. | Baseline and up to 46 weeks | 
| Percentage of Participants Who Completed or Discontinued From the Study | 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. | Up to 50 weeks | 
| 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 | 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. | From the start of study treatment until follow-up (up to 50 weeks) |