A Dose-Finding Study of Topiramate (JNS019) in Participants With Migraine

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine a recommended dose of topiramate in participants with migraine (type of severe headache that occurs periodically and is often associated with nausea, vomiting, and constipation or diarrhea), to verify the superiority (statistically more effective) of the drug to placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial), and to assess if a same therapeutic effect can be observed between this study and overseas Caucasian clinical studies.

Detailed Description
-----------------
This study is a multicenter (more than 1 site), placebo-controlled (compared to placebo), randomized (participants assigned study drug by chance), double-blind (neither the participant nor the physician know the assigned study drug), parallel-group comparison (comparison for each group at the same time) study. The study period consists of 4 phases: the observation phase, double-blind phase, exit period and follow-up period. After the double-blind phase, the participants will be transferred to the continuous treatment study. The observation phase which is started after informed consent consists of the washout period (non-treatment period with migraine preventive medication: at least 2 weeks) and baseline determination period (at least 4 weeks). The participants who complete the observation phase and meet the inclusion criteria will be randomly assigned to the topiramate 50 milligram (mg) group, topiramate 100-mg group or placebo group after registration. The double-blind phase consists of the titration period (dose-escalation, 4 weeks) and fixed-dose period (18 weeks). In the titration period, starting from 1 topiramate 25-mg tablet or 1 topiramate 25-mg placebo tablet once daily (1 tablet in the evening), the dose will be increased by 1 tablet every week up to twice daily (2 tablets in the morning, 2 tablets in the evening). After that, the twice-daily treatment (2 tablets in the morning, 2 tablets in the evening) will be continued for 7 days from Day 22 to Day 28. In the fixed-dose period, the topiramate 25-mg tablets or topiramate 25-mg placebo tablets at the same dose as that in the final treatment in titration period will be continued. The participants who are not transferred to the continuous treatment study after completion of the double-blind phase or after discontinuation during the double-blind phase will be transferred to the exit period (up to 1 week).The participants who complete the exit period will be transferred to the follow-up period, and a follow-up of the participant's safety and headache symptoms such as the migraine period rate will be conducted for 4 weeks after the completion of investigational treatment. Meanwhile, the participants who complete the double-blind phase or those who discontinue the study at Week 4 or later in the fixed-dose period during the double-blind phase due to lack of efficacy and give consent to transfer to the continuous treatment study will be transferred to the transfer period (up to 3 weeks) under blind conditions.

Official Title
-----------------
A Placebo-Controlled Dose-Finding Study of JNS019 (Topiramate) in Migraine Patients

Conditions
-----------------
Migraine

Intervention / Treatment
-----------------
* Drug: Topiramate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants who meet the Second Edition of the International Classification of Headache Disorders (ICHD-II), 1.1 Migraine without aura or 1.2 Migraine with aura over at least 6 months before the time of informed consent Participants who had an average of no more than 8 migraine attacks per month during 3 months before informed consent and an average of no more than 14 headache (migraine and non-migraine) days Participants whose number of migraine attacks during the baseline determination period (28 days) is 3 to 12 according to the 24-hour rule and number of headache days (migraine and non-migraine) is no more than 14 Participants who took no migraine preventive medications over 2 weeks before informed consent, or who can take at least 2-week washout period before baseline determination period if they are taking migraine preventive medications Female participants must be postmenopausal, surgically sterile, abstinent, or can take adequate contraceptive measures after informed consent and continue it to the completion of investigational treatment Exclusion Criteria: Participants who cannot distinguish between migraine and non-migraine headache Participants with headache other than those described in the ICHD-II, 1.1 Migraine without aura, 1.2 Migraine with aura, 2. Tension headache or 11.5 Sinus headache If the participant has received drug therapies for prevention of migraine, the discontinued preventive therapies due to insufficient efficacy should be at least three types Participants who excessively took medications for migraine attacks such as analgesics (drug used to control pain) as medications to be taken as needed within 3 months before informed consent Participants who have taken topiramate (test drug in this study) in the past

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topiramate (JNS019) 50 mg<br>In titration period, topiramate 25 milligram (mg) tablet will be given once daily in evening orally for 7 days; then topiramate 25 mg tablet twice daily orally from Day 8 to Day 14; then topiramate 25 mg tablet twice daily along with matching placebo tablet once daily in the evening orally from Day 15 to Day 21; then topiramate 25 mg tablet along with matching placebo tablet twice daily orally from Day 22 to Day 28 and will be continued further for 18 weeks in the fixed dose period. | Drug: Topiramate<br>* In the titration period, topiramate 25-mg tablet once daily orally for 1 week, the dose will be increased by 1 tablet every week up to twice daily for a total of 4 weeks so that the total daily dose given is 50 mg or 100mg. The dose given in the final titration week will be continued for further 18 weeks (fixed dose period).<br>Drug: Placebo<br>* In the titration period, matching placebo tablet once daily orally for 1 week, the dose will be increased by 1 tablet every week up to twice daily for a total of 4 weeks. The dose given in the final titration week will be continued for further 18 weeks (fixed dose period).<br>|
| Experimental: Topiramate 100 mg<br>In titration period, topiramate 25 mg tablet will be given once daily in the evening orally for 7 days; then topiramate 25 mg tablet twice daily orally from Day 8 to Day 14; then topiramate 25 mg tablet twice daily (1 tablet in the morning and 2 tablets in the evening) orally from Day 15 to Day 21; then 2 topiramate 25 mg tablets twice daily orally from Day 22 to Day 28 and will be continued further for 18 weeks in the fixed dose period. | Drug: Topiramate<br>* In the titration period, topiramate 25-mg tablet once daily orally for 1 week, the dose will be increased by 1 tablet every week up to twice daily for a total of 4 weeks so that the total daily dose given is 50 mg or 100mg. The dose given in the final titration week will be continued for further 18 weeks (fixed dose period).<br>|
| Placebo Comparator: Placebo<br>In titration period, matching placebo tablet will be given once daily in evening orally for 7 days; followed by matching placebo tablet twice daily orally from Day 8 to Day 14; followed by matching placebo tablet twice daily (1 tablet in the morning and 2 tablets in the evening) orally from Day 15 to Day 21; followed by 2 matching placebo tablets twice orally from Day 22 to Day 28 and will becontinued further for 18 weeks in the fixed dose period. | Drug: Placebo<br>* In the titration period, matching placebo tablet once daily orally for 1 week, the dose will be increased by 1 tablet every week up to twice daily for a total of 4 weeks. The dose given in the final titration week will be continued for further 18 weeks (fixed dose period).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Monthly Migraine Attacks (According to 24-Hour Rule) Through Month 6 | As per 24-hour rule, if symptom of pain due to migraine continues for more than 24 hours, it should be considered as 2 or more migraine attacks considering the maximum duration up to 24 hours. If the interval between latest migraine attack (ending time) and previous migraine attack (onset time) is less than 24 hours, 2 migraine attacks should be considered as 1 migraine attack. If the onset of migraine was prevented by a rescue drug, it should be considered as 1 migraine attack even if aura had started. Mean change was calculated by subtracting baseline value from the mean of 6 months value. | Baseline (28 days before randomization) through Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Number of Monthly Migraine Attack Days at Month 1, 2, 3, 4, 5 and 6 | Migraine is a headache disorder with 2 subtypes: migraine without aura (at least 5 attacks lasting 4-72 hours with at least 2 following characteristics: unilateral location, pulsating quality, moderate/severe pain and either nausea/vomiting or photophobia and phonophobia) and migraine with aura (reversible focal neurological symptoms that develop over 5-20 minutes and last for less than 60 minutes); average at given month was calculated by dividing total number of migraine attack days until that month by the total number of days of assessment, multiplied by 28 (a month was equal to 28 days). | Baseline (28 days before randomization), Month 1, 2, 3, 4, 5 and 6 | 
| Change From Baseline in Average Number of Monthly Headache Days at Month 1, 2, 3, 4, 5 and 6 | Headache days were the days when at least 30-minute migraine and non-migraine headache occurred and were calculated from the headache diaries kept by the participants. Average at given month was calculated by dividing total number of headache days until that month by the total number of days of assessment, multiplied by 28 (a month was equal to 28 days). | Baseline (28 days before randomization), Month 1, 2, 3, 4, 5 and 6 | 
| Change From Baseline in Average Number of Monthly Migraine Attacks (According to the Diagnostic Criteria of the International Headache Society) at Month 1, 2, 3, 4, 5 and 6 | Migraine is a headache disorder with 2 subtypes: migraine without aura (at least 5 attacks lasting 4-72 hours with at least 2 following characteristics: unilateral location, pulsating quality, moderate/severe pain and either nausea/vomiting or photophobia and phonophobia) and migraine with aura (reversible focal neurological symptoms that develop over 5-20 minutes and last for less than 60 minutes); average at given month was calculated by dividing total number of migraine attacks until that month by the total number of days of assessment, multiplied by 28 (a month was equal to 28 days). | Baseline (28 days before randomization), Month 1, 2, 3, 4, 5 and 6 | 
| Change From Baseline in Monthly Migraine Attacks (According to 48-Hour Rule) at Month 1, 2, 3, 4, 5 and 6 | As per 48-hour rule, if the symptom of pain due to migraine continues for more than 48 hours, it should be considered as 2 or more migraine attacks considering the maximum duration up to 48 hours. If the interval between the latest migraine attack (ending time) and the previous migraine attack (onset time) is less than 48 hours, the 2 migraine attacks should be considered as 1 migraine attack. If the onset of the migraine was prevented by a rescue drug, it should be considered as 1 migraine attack even if the aura had started. | Baseline (28 days before randomization), Month 1, 2, 3, 4, 5 and 6 | 
| Change From Baseline in Migraine Attacks (According to 24-Hour Rule) Over Week 19 to Week 22 Period | The change from baseline in average number of migraine attacks (as per 24-hour rule) over Week 19 to Week 22 period was calculated by subtracting the baseline value from the average value of the Week 19 to Week 22 period. | Baseline (28 days before randomization), Week 19 to Week 22 Period | 
| Average Number of Rescue Drug Treatment Days | Rescue medications are administered to participants when efficacy of study drug is not satisfactory, or effect of study drug is too great and is likely to cause a hazard to participant, or to manage an emergency situation. If an aura of migraine, a migraine attack or a non-migraine headache attack occurred during the study period, use of following rescue drugs was permitted: analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), ergotamines, triptans and anti-emetics (drug used to stop vomiting). Average at baseline was calculated by dividing total number of rescue drug treatment days until baseline by the total number of days of assessment, multiplied by 28 (a month was equal to 28 days). | Baseline (28 days before randomization) | 
| Change From Baseline in the Average Number of Rescue Drug Treatment Days at Month 6 | Rescue medications are medicines that may be administered to the participants when efficacy of study drug is not satisfactory, or the effect of study drug is too great and is likely to cause a hazard to the participant, or to manage an emergency situation. If an aura of migraine, a migraine attack or a non-migraine headache attack occurred during the study period, use of following rescue drugs was permitted: analgesics, NSAIDs, ergotamines, triptans and anti-emetics. Average at Month 6 was calculated by dividing total number of rescue drug treatment days until that month by the total number of days of assessment, multiplied by 28 (a month was equal to 28 days). | Month 6 | 
| Percentage of Participants With Response to Study Treatment | Responders were the participants who had at least 50 percent reduction in the average number of monthly migraine attacks. | Month 1, 2, 3, 4, 5 and 6 | 
| Short Form-36 Health Survey (SF-36) Score | The SF-36 is a survey of participant health. It consists of 8 scaled scores, which are weighted sums of the questions in their section. The 8 sections are: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health. Each item is scored on a 0-100 range so that total score ranges from 0-100 with high score indicating more favorable health state. Final evaluation was done at Day 155 or at discontinuation for those participants who discontinued before Day 155. | Baseline (28 days before randomization), Day 29, 85 and final evaluation (FE) (Day 155/early withdrawal [EW]) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Topiramate, Migraine