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.

Eligibility Criteria:
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.