Treximet Trademark (TM) in the Prevention and Modification of Disease Progression in Migraine

Study Overview
=================
Brief Summary
-----------------
This study is being conducted to evaluate the hypothesis that use of pharmacological and non-pharmacological interventions may allow subjects at high risk for chronic migraine to avoid or reverse the transformation of episodic migraine to chronic migraine.

Detailed Description
-----------------
Two investigative centers will enroll 40 subjects in the United States. Subject participation in the 5 visit study will last 4 months. At Visit 1, following informed consent, a medical, migraine, and medication history will be collected and a physical and neurological exam with vital signs will be performed. An electrocardiogram (ECG) will be completed. A Lifestyle Choices for Better Migraine Management Questionnaire (Lifestyle Questionnaire) will be completed. Eligible subjects then complete a 1-month Baseline Period and treat migraine with their current preferred treatment of choice, documenting headache severity and associated symptoms in a 30-day Baseline Diary. At Visit 2, the Baseline Diary will be reviewed and a pregnancy test will be collected from all subjects of childbearing potential. Vital signs will be collected and Adverse Events documented. Subjects continuing to meet eligibility criteria will be randomized 1:1 to Treximet or naproxen and provided with study medication to treat on 14 or fewer days per month. Subjects will be encouraged to treat their migraine attacks within 1 hour of onset of headache pain and while the pain is still mild. Subjects will view an educational digital video disc (DVD) concerning lifestyle modification, receive a copy for home viewing, complete the Lifestyle Questionnaire, and receive 3 copies of the Lifestyle Questionnaire for weekly completion between Visits 2 and 3. The Migraine Disability Assessment questionnaire (MIDAS) will be completed and a 30-day Treatment Period Diary will be dispensed. At Visits 3 and 4, Adverse Events will be collected, completed Diaries will be reviewed, and Drug Accountability performed. Pregnancy tests will be collected from all subjects of childbearing potential. Vital signs will be collected. Completed Lifestyle Questionnaires will be collected, a Lifestyle Questionnaire will be completed in the office, and 3 copies will be dispensed for weekly completion between visits. Study medication for the following month will be dispensed with a 30-day Diary. At Visit 5, Adverse Events will be collected, completed Diaries will be reviewed, and Drug Accountability performed. Pregnancy tests will be collected from all subjects of childbearing potential. Vital signs will be collected. Completed Lifestyle Questionnaires will be collected and a Lifestyle Questionnaire will be completed in the office. Subjects will complete the MIDAS before exiting the study.

Official Title
-----------------
TreximetTM in the Prevention and Modification of Disease Progression in Migraine

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

Intervention / Treatment
-----------------
* Drug: Sumatriptan/Naproxen Sodium
* Drug: Naproxen Sodium


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject Is male or female, in otherwise good health, 18 to 65 years of age. Has history of frequent episodic migraine (6-14 migraine days per month) (with or without aura) according to the 2nd Edition of The International Headache Classification (ICHD-2) for at least 3 months. (Stage 2-3 frequent transforming migraine) Had onset of migraine before age 50. Is able to differentiate migraine from any other headache they may experience (e.g., tension-type headache). Has stable history of headache at least 3 months prior to screening. Is not currently taking a migraine preventive or has been taking preventive for at least 30 days prior to screening and agrees to not start, stop, or change medication and/or dosage during the study period. Has at least 50% of migraine attacks beginning at mild severity. If female of childbearing potential, has a negative urine pregnancy test at Visits 1-5 and uses, or agrees to use, for the duration of the study, a medically acceptable form of contraception as determined by the investigator. Complete abstinence from intercourse from 2 weeks prior to administration of study drug throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the study drug (a minimum of 7 days); or, Surgically sterile (hysterectomy or tubal ligation or otherwise incapable of pregnancy); or, Sterilization of male partner; or, Intrauterine device with published data showing lowest expected failure rate is less than 1% per year; or, Double barrier method (i.e., 2 physical barriers OR 1 physical barrier plus spermicide) for a least 1 month prior to Visit 1 and throughout study; or, Hormonal contraceptives for at least 3 months prior to Visit 1 and throughout study. Had 6 or more migraine treatment days in 1 month prior to Visit 2. Exclusion Criteria: Subject Is unable to understand the study requirements, the informed consent, or complete headache records as required per protocol. Is pregnant, actively trying to become pregnant, or breast-feeding. Has experienced the following migraine variants: basilar migraine, aura without headache, familial hemiplegic migraine, complicated migraine, ophthalmoplegic migraine and retinal migraine. Has a history of Medication Overuse Headache in the 3 months prior to study enrollment or during the baseline phase Has history of acute migraine treatment greater than14 days per month in 3 months prior to screening. Has abused, in the opinion of the Investigator, any of the following drugs, currently or within the past 1 year: opioids alcohol barbiturates benzodiazepine cocaine Has history of impaired hepatic or renal function that, in the investigator's opinion, contraindicates participation in this study. Has an unstable neurological condition or a significantly abnormal neurological examination with focal signs or signs of increased intracranial pressure. Suffers from cardiovascular disease (ischemic heart disease, including angina pectoris, myocardial infarction, documented silent ischemia, or with Prinzmetal's angina); has symptoms of ischemic heart disease, ischemic abdominal syndromes, peripheral vascular disease or Raynaud's Syndrome; has uncontrolled hypertension (≥140/90 millimeters of mercury (mmHg) in 2 out of 3 blood pressure (BP) measurements at screening); has electrocardiogram (ECG) results outside normal limits for clinically stable patients as judged by the investigator. Has a history of asthma and nasal polyps. Has a history of peptic ulcer disease requiring therapeutic intervention in the year prior to study enrollment Has evidence or history of any gastrointestinal (GI) surgery or GI ulceration or perforation of the stomach or intestine in the past 6 months, gastrointestinal bleeding in the past year or evidence or history of inflammatory bowel disease or history of any other bleeding disorder, or has taken or plans to take any anti-coagulant or any antiplatelet agent within the 2 weeks prior to screening through 48 hours post final study treatment. Has history of non-steroidal anti-inflammatory drug induced gastritis, esophagitis, or duodenitis. Suffers from a serious illness, or an unstable medical condition, one that could require hospitalization, or could increase the risk of adverse events. Has in the opinion of the investigator a significant cardiovascular risk profile that may include uncontrolled high blood pressure, post-menopausal women, male over 40 years old, hypercholesterolemia, obesity, diabetes mellitus, smoking, or a family history of cardiovascular disease in a 1st degree relative. Has in the opinion of the investigator a significant cerebrovascular risk profile that may include female over the age of 35 using oral birth control, smoking, or a family history of cerebrovascular disease in a first degree relative. Has a psychiatric condition, in the opinion of the investigator that may affect the interpretation of efficacy and safety data or contraindicates the subject's participation in the study. Has hypersensitivity, intolerance, or contraindication to the use of sumatriptan, any of its components, or any other 5-hydroxytryptamine 1 (5-HT1) agonist. Has a hypersensitivity, intolerance, or contraindication to the use of naproxen, any of its components, or any other non-steroidal anti-inflammatory drug including aspirin and cyclooxygenase-2 (COX-2) inhibiting agents. Is currently taking a migraine prophylactic medication containing an ergotamine or ergot derivative such as dihydroergotamine (DHE) or methysergide. Has taken, or plans to take, a monoamine oxidase inhibitor (MAOI) including herbal preparations containing St. John's wort (Hypericum perforatum), anytime within the 2 weeks prior to screening through 2 weeks post final study treatment. Has taken or plans to take an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) anytime within the 2 weeks prior to screening through 48 hours post final study treatment. Has received any investigational agents within 30 days prior to Visit 1. Plans to participate in another clinical study at any time during this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sumatriptan/Naproxen Sodium<br>In Treatment Period, subjects randomized to Sumatriptan/Naproxen Sodium will be provided with 14 tablets of Sumatriptan/Naproxen Sodium to treat migraine within 1 hour of onset on 14 or fewer days per month. Subjects will be provided with 14 tablets of Sumatriptan/Naproxen Sodium per month for rescue of persistent or recurring headache. | Drug: Sumatriptan/Naproxen Sodium<br>* Each tablet of Treximet for oral administration contains Sumatriptan 85mg / Naproxen Sodium 500mg. Study medication is to be administered within 1 hour of migraine onset on 14 or fewer days per month in the Treatment Period.<br>* Other names: Treximet;|
| Active Comparator: Naproxen Sodium<br>In Treatment Period, subjects randomized to Naproxen Sodium 500mg will be provided with 14 tablets of Naproxen Sodium to treat migraine within 1 hour of onset on 14 or fewer days per month. Subjects will be provided with 14 tablets of Naproxen Sodium per month for rescue of persistent or recurring headache. | Drug: Naproxen Sodium<br>* Each tablet of Naproxen Sodium for oral administration is provided in 500mg tablet. Study medication is to be administered within 1 hour of migraine onset on 14 or fewer days per month in the Treatment Period.<br>* Other names: Naproxen;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change of Headache Days Compared to Baseline | Comparing the number of migraine headache days during Baseline Period Days 1-30 to number or migraine headache days reported in Treatment Period Days 91-120 in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. Percent change=[ (total headache days during Treatment Period Month 3 (Days 91-120)-total headache days during Baseline (Days 1-30)/total headache days during Baseline (Days 1-30)]*100%). | Day 121 (following 30 day Baseline Period and Treatment Period Days 91-120) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Migraine Attacks | Comparing the number of migraine attacks reported from Baseline to the number of migraine attacks reported in Treatment Period Months 1(Days 31-60), 2(Days 61-90), and 3(Days 91-120) in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. Each treatment month percent change was individually compared to Baseline. The following formula was used for each treatment period calculation. e.g.,Percent change=[ (total migraine attacks days during Treatment Period Month 3 (Days 91-120)-total migraine attacks during Baseline (Days 1-30)/total migraine attacks during Baseline (Days 1-30)]*100%). | Baseline Period collected at Day 31, Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Migraine Severity | Comparing migraine severity 2 hours after treatment from Baseline(Days 1-30) to migraine severity reported 2 hours after treatment in Treatment Period Months 1 (Days 31-60), 2(Days 61-90), and 3(Days 91-120) in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. Percent change was calculated by determining percent change in each subject, from Treatment Period Month 3 and Baseline, then comparing the average change between each arm. The following formula was used for each treatment period calculation. e.g.,Percent change=[ (mean migraine severity during Treatment Period Month 3 (Days 91-120)- mean migraine severity during Baseline (Days 1-30)/mean migraine severity during Baseline (Days 1-30)]*100%). | Baseline Period collected at Day 31, Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Migraine Duration From Onset to Pain Free | Comparing mean migraine duration from onset to painfree from Baseline(Days 1-30) to each month: Treatment Period Months 1 (Days 31-60), 2(Days 61-90), and 3(Days 91-120) in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. Percent change was calculated by determining percent change in each subject, from Treatment Period Month 3 and Baseline, then comparing the average change between each arm. The following formula was used for each treatment period calculation. e.g.,Percent change=[(mean duration from onset to painfree during Treatment Period Month 3 (Days 91-120)- mean duration from onset to painfree during Baseline (Days 1-30)/mean duration from onset to painfree during Baseline (Days 1-30)]*100%). | Baseline Period collected at Day 31, Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Migraine Duration From Time of Treatment to Pain Free | % change from Baseline in mean migraine duration from time of treatment to pain free reported in Treatment Period Months 1, 2, and 3 in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. Percent change=[(mean duration from treatment to painfree during Treatment Period Month 3 (Days 91-120)- mean duration from treatment to painfree during Baseline (Days 1-30)/mean duration from treatment to painfree during Baseline (Days 1-30)]*100%). | Baseline Period collected at Day 31, Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Headache Days With Greater Than 50% Reduction | Number of subjects with at least a 50% reduction in number of headache days reported in Baseline versus Treatment period Months 1, 2, and 3 in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. | Baseline Period collected at Day 31, Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Migraine Attacks With 50% Reduction | Number of subjects with at least a 50% reduction in number of migraine attacks reported in Baseline versus Treatment period Months 1, 2, and 3 in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm | Baseline Period collected at Day 31, Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Doses of Study Medication | Total number of doses of study medication reported taken per participant in Treatment Period Months 1, 2, and 3 in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. | Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Percent Change of Doses of Study Medication | % change in number of doses during Baseline of triptans (Group A) and non-steroidal anti-inflammatory drugs(NSAIDs) (Group B) vs. doses during Treatment Period Months 1, 2, and 3 of study medication in the Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. e.g.,Percent change=[(number of doses during Treatment Period Month 3 (Days 91-120)- number of doses during Baseline (Days 1-30)/number of doses during Baseline (Days 1-30)]*100%). The total number of subjects used in this analysis is different than the total number of subjects as the analysis is only looking at those subjects that were taking one of the study medications during Baseline. | Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 
| Migraine Disability Assessment Test (MIDAS) | Change in MIDAS total score from end of Baseline (Day 31) to end Treatment Period month 3 (Day 121) in the Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. Total score of disability ranges: 0 to 5, MIDAS Grade I, Little or no disability 6 to 10, MIDAS Grade II, Mild disability 11 to 20, MIDAS Grade III, Moderate disability 21+, MIDAS Grade IV, Severe disability No subscales are present. | Baseline MIDAS collected at Day 31, Post final dose study medication MIDAS collected at Day 121. | 
| Compliance With Lifestyle Changes | Self-assessed grade of compliance with lifestyle modification changes (where A=1, B=2, C=3, D=4, and F=5; lower scores represent better outcomes) in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. | Day 121 | 
| Percent Change in Headache Days All Treatment Periods Compared to Baseline | Comparing the number of migraine headache days during Baseline Period Days 1-30 to number or migraine headache days reported in Treatment Period Month 1 (Days 31-60), Treatment Period Month 2 (Days 61-90), and Treatment Period Month 3 (Days 91-120) in Sumatriptan/Naproxen Sodium arm vs. Naproxen Sodium arm. e.g., Percent change=[ (total headache days during Treatment Period Month 3 (Days 91-120)-total headache days during Baseline (Days 1-30)/total headache days during Baseline (Days 1-30)]*100%). | Baseline Period collected at Day 31, Treatment Period Months 1, 2, and 3 collected at Days 61, 91, and 121. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Frequent migraine, Migraine transformation, Migraine, Treximet, Naproxen, Sumatriptan