CGRP, Estrogen, Cortisol, VIP, α-Amylase, PGE2, PGI2 and ß-Endorphin Levels in Menstrual Migraine Before and After Treximet
CGRP, Estrogen, Cortisol, VIP, α-Amylase, PGE2, PGI2 and ß-Endorphin Levels in Menstrual Migraine Before and After Treximet
The purpose of this study is to (1) evaluate pain-free efficacy of Treximet™ following
 treatment of menstrual migraine, (2) investigate levels of Calcitonin gene-related peptide
 (CGRP), estrogen, cortisol, vasoactive intestinal peptide (VIP), alpha (a)-amylase,
 Prostaglandin E2 (PGE2), Prostaglandin I2 (PGI2) and beta (ß)-endorphin in saliva before and
 after Treximet™, (3) evaluate efficacy of Treximet™ to return to baseline levels following
 treatment, and (4) correlate estrogen in saliva vs. urinary estradiol at mid-luteal, onset of
 menstrually-related migraine, and after successful treatment with Treximet™.
This double-blind multi-site study will be conducted to enroll 40 evaluable participants. All
 subjects will be medically stable at enrollment and be on a stabilized dosage of daily
 medications.

 At Visit 1 (Baseline) following Informed Consent, a physical and neurological exam, baseline
 electrocardiogram (ECG), and vital signs will be completed. A urine pregnancy test will be
 collected by all subjects of childbearing potential. Routine labs (electrolyte panel with
 creatinine, alanine aminotransferase (ALT) / aspartate aminotransferase (AST), a luteinizing
 hormone (LH) lab (for menstrual cycle staging) and a baseline saliva sample (for CGRP,
 estrogen, cortisol, VIP, a-amylase, PGI2, PGE2 and β-endorphin analysis) will be collected.
 Subjects should be headache-free at Visit 1. A medical, headache, and medication history will
 be collected on all subjects and eligible subjects will be randomized 1:1 to Group A or Group
 B. Group A will receive Treximet™ (sumatriptan succinate 85 milligrams (mg) and naproxen
 sodium 500 mg) 1 tablet. Group B will be provided 1 matching placebo tablet. Subjects will be
 instructed to not start study medication until notified by study staff that lab results were
 normal and they are eligible to proceed. Subjects will be instructed to treat as early as
 possible following the onset of a typical menstrual headache. Groups A and B will be provided
 with Treximet™ 1 tablet for rescue between 2 and 24 hours for persistent or recurring
 headache. Subjects will receive a Diary and instructions on Digital Versatile Disc (DVD)
 regarding documentation. Migraine associated symptoms (ie nausea, vomiting, light
 sensitivity, or sound sensitivity) will be collected as well as sleeplessness, difficulty
 thinking other bodily pain, and menstrual associated symptoms (to include intensity of
 menstrual cramps).

 Subjects will be given kits with written instructions for collection of urine and saliva
 samples and additional saliva instructions on DVD. All subjects will be given LH testing kits
 to define the time of ovulation. Diary documentation begins at the time of ovulation. They
 will collect baseline saliva and first morning urine samples during the mid-luteal time
 period for two consecutive days, which is defined as 4-7 days after the LH surge. Subjects
 will also be instructed to begin collection of saliva 48 hours prior to the start of menses
 at 8:00 am, 2:00 pm, and 8:00 pm for two days or until menstrual migraine occurs. They also
 will collect a first morning urine sample on the two mornings prior to menses. At the point
 of headache onset, subjects will be instructed to collect saliva at onset of pain, time of
 treatment, 2 and 24 hours following treatment, at pain free, 2 hours after pain free, and 24
 hours after pain free. Subjects will also be instructed to collect a urine specimen when they
 are pain free following treatment with study medication. Subjects will document migraine
 associated symptoms, menstrual associated symptoms, and recurrence symptoms at all saliva
 collection time points in the provided Diary per instruction.

 Subjects should be instructed to phone the study coordinator at the end of the menstrual
 cycle to return for Visit 2 within 7 days.

 _________________________

 At Visit 2 (Review) Diaries will be reviewed and frozen saliva and urine samples will be
 returned to the clinic. Subjects must meet the following criteria for urine and saliva
 analysis:

 -  Diary review indicates that headache would have, if left untreated, at least one symptom
 of migraine (nausea, vomiting, phonophobia, or photophobia) . And

 -  Headache was associated with the onset of menses

 And

 • Saliva and urine samples are returned to the clinic.

 Medical and medication history will be updated and adverse events collected. A urine
 pregnancy test will be collected by all subjects of childbearing potential. Drug
 accountability and compliance will be assessed.
Inclusion Criteria:

 Subject

 1. is female between the ages of 18-45 and, if of child-bearing potential, has a negative
 pregnancy test (urine or serum) at screen, and agrees to one of the following:

 -  Complete abstinence from intercourse from 2 weeks prior to administration of the
 investigational product, throughout the study, and for a time interval (5 days)
 after completion or premature discontinuation from the study,

 -  History of bilateral tubal ligation

 -  Sterilization of male partner; or,

 -  Implants of levonorgestrel; or,

 -  Injectable progestogen; or,

 -  Oral contraceptive (combination therapy with ethinyl estradiol plus a progestin)
 with a placebo week every 1-3 months; or,

 -  Any intrauterine device (IUD) with published data showing that the highest
 expected failure rate is less than 1% per year (not all IUDs meet this
 criterion); or,

 -  Spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a
 female diaphragm); or,

 -  Any other barrier methods (only if used in combination with any of the above
 acceptable methods); or,

 -  Any other methods with published data showing that the highest expected failure
 rate for that method is less than 1% per year.

 2. is formally diagnosed with International Classification of Headache Disorders (ICHD)
 menstrual migraine

 3. has regular and predictable monthly menstrual cycles within a range of 22-32 days for
 the past 3 cycles.

 4. has fewer than 15 headache days per month in past 3 months

 5. has headache that, if left untreated, would have at least 1 symptom of migraine
 (nausea, vomiting, photophobia, or phonophobia) or respond to a triptan or
 ergotamine-containing medication with at least 50% of headaches

 6. has a history of reliably predicting menstrual migraine headache onset at least 70% of
 the time

 7. is medically stable as determined by the Investigator

 8. if taking any concomitant medications, is on a stabilized dosage at the discretion of
 the investigator

 9. is able to understand and communicate intelligibly with the study observer

 10. is able to take oral medication, adhere to the medication regimens and perform study
 procedures

 11. is able to read and comprehend written instructions and be willing to complete all
 procedures and assessments required by this protocol

 12. is able to demonstrate the willingness to participate by signing and understanding an
 informed consent after full explanation of the study

 Exclusion Criteria:

 Subject

 1. has a history of serotonin syndrome.

 2. has any medical condition that, in the opinion of the investigator, could alter the
 response to study medication or confound the results of the study (ie. pathology of
 the salivary glands such as viral or bacterial sialadenitis or obstructive
 sialadenitis or Sjögren's Syndrome)

 3. is of childbearing potential and not using adequate contraceptive measures

 4. has history of retinal, basilar or hemiplegic migraine, cluster headache, or secondary
 headaches (such as due to trauma, infection, alterations of homeostasis, ear, nose and
 throat (ENT) or psychiatric disorders, cranial or cervical disorders or neuralgias)

 5. in the investigator's opinion, is likely to have unrecognized cardiovascular or
 cerebrovascular disease (based on history or the presence of risk factors including
 but not limited to, hypertension, hypercholesterolemia, smoker, obesity, diabetes, or
 family history of coronary artery disease)

 6. has blood pressure equal to or greater than 160/90 millimeters of mercury (mmHg) in 2
 out of 3 blood pressure (BP) measurements at screening or is taking any
 angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker

 7. has a history of significant congenital heart disease, cardiac arrhythmias requiring
 medication, or a history of a clinically significant electrocardiogram abnormality
 that, in the investigator's opinion, contraindicates participation in this study

 8. has evidence or history of any ischemic vascular diseases including: ischemic heart
 disease, ischemic abdominal syndromes, peripheral vascular disease or Raynaud's
 Syndrome, or signs/symptoms consistent with any of the above

 9. has evidence or history of central nervous system pathology including stroke and/or
 transient ischemic attacks (TIAs), epilepsy or structural brain lesions which lower
 the convulsive threshold; or has been treated with an antiepileptic drug for seizure
 control within 5 years prior to screening

 10. has a history of impaired hepatic or renal function that, in the investigator's
 opinion, contraindicates participation in this study

 11. has hypersensitivity, intolerance, or contraindication to the use of any triptan,
 non-steroidal anti-inflammatory drug (NSAID) or aspirin (including all sumatriptan and
 naproxen preparations) or has nasal polyps and asthma

 12. is currently taking, or has taken in the previous three months, a migraine
 prophylactic medication containing methysergide; or is taking a migraine or menstrual
 migraine prophylactic medication that is not stabilized (eg. Perimenstrual use of
 triptans and estradiol patches)

 13. has a recent history of regular use of opioids or barbiturates for treatment of their
 migraine headache and/or other non-migraine pain or any medication overuse that in the
 opinion of the investigator has exacerbated or contributed to the current headache
 pattern of the subject. Overuse is defined as an average of 10 days per month over the
 last 6 months.

 14. 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.

 15. is currently taking and plans to continue an oral steroid any time from screening
 through onset of menses that will be treated with study medication (at the discretion
 of the investigator)

 16. has history of any bleeding disorder or is currently taking any anti-coagulant or any
 antiplatelet agent.

 17. has evidence or history of any gastrointestinal surgery or gastrointestinal (GI)
 ulceration or perforation in the past six months, gastrointestinal bleeding in the
 past year; or evidence or history of inflammatory bowel disease

 18. is pregnant, actively trying to become pregnant, or breast feeding

 19. has evidence of alcohol or substance abuse within the last year or any concurrent
 medical or psychiatric condition which, in the investigator's judgment, will likely
 interfere with the study conduct, subject cooperation, or evaluation and
 interpretation of the study results, or which otherwise contraindicates participation
 in this clinical trial.

 20. has participated in an investigational drug trial within the previous four weeks or
 plans to participate in another study at any time during this study.