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

 1. 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,

 2. Surgically sterile (hysterectomy or tubal ligation or otherwise incapable of
 pregnancy); or,

 3. Sterilization of male partner; or,

 4. Intrauterine device with published data showing lowest expected failure rate is
 less than 1% per year; or,

 5. 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,

 6. 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:

 1. opioids

 2. alcohol

 3. barbiturates

 4. benzodiazepine

 5. 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.