A Study of Combination Product (Sumatriptan Succinate and Naproxen Sodium) in Migraine Subjects Who Report Poor Response or Intolerance to Short Acting Triptans (Study 1 of 2)

This is a randomized, double-blind, placebo-controlled, crossover, two-attack, out-patient, early-intervention evaluation of subjects who have migraine with or without aura and who discontinued use of short acting triptan(s) within the past year due to non-response or intolerance. Subjects will treat 2 separate migraine attacks during the mild phase of each attack; one attack will be treated with one tablet of the Combination Product (sumatriptan succinate and naproxen sodium) and the other attack with one tablet of placebo (crossover design); however, the order of these treatments will be randomized. A minimum 1-week washout period is required between study medication treatment of the first and second migraine attacks.

Each subject will have two visits: (1) a Screening visit at study entry and (2) a Final visit 4-10 days after the second (or last) attack. A telephone contact will also be required 1-3 days after the first attack, and then once per month until the Final visit.

The primary study objective is to assess efficacy as measured by sustained pain-free (SPF) relief of Combination Product compared to placebo in treating migraine subjects who have previously discontinued treatment with short acting triptans (rizatriptan, sumatriptan, almotriptan, zolmitriptan, and eletriptan).

Inclusion criteria

• Subject is male or female between 18 and 65 years old.
• Subject has migraine with or without aura (2004 ICHD-II criteria).
• Subject has 1-8 migraines per month over the previous 3 months and less than 15 total headache days per month.
• Subject has recently (within 1 year) discontinued the use of eletriptan, rizatriptan, sumatriptan, almotriptan, or zolmitriptan, due to nonresponse or intolerable adverse events. Non-response is defined as documented discontinuation of treatment with eletriptan, rizatriptan, sumatriptan, almotriptan, or zolmitriptan for reasons related to response, including (but not limited to): slow onset of efficacy, inconsistent efficacy, inadequate overall efficacy, or inadequate sustained efficacy through 24 hours. Intolerance is defined as documented discontinuation of treatment with eletriptan, rizatriptan, sumatriptan, almotriptan, or zolmitriptan for other reasons, attributable to the triptan, outside of non-response.

A female is eligible to enter and participate in this study if she is of:

• non-childbearing potential (i.e., physiologically incapable of becoming pregnant); or,
• child-bearing potential, has a negative urine pregnancy test at screen, and agrees to one of the following acceptable measures of contraception:
• Complete abstinence from intercourse from 2 weeks prior to administration of the investigational product, throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the investigational drug (a minimum of 5 days); subjects utilizing this method must agree to use an alternate method of contraception if they should become sexually active and will be queried on whether they have been abstinent in the preceding 2 weeks when they present to the clinic for the Final Visit; or,
• Female sterilization; or,
• Sterilization of male partner; or,
• Implants of levonorgestrel; or,
• Injectable progestogen; or,
• Oral contraceptive (combined or progestogen only); 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 methods with published data showing that the highest expected failure rate for that method is less than 1% per year; or,
• Any other barrier methods only if used in combination with any of the above acceptable methods.
• Subject taking oral contraceptives has been on a stable regimen for at least 2 months prior to screening.
• Subject is willing and able to provide informed consent prior to entry into this treatment phase of the study.
• Subject is able to understand and complete the diary card.

Exclusion criteria

Subjects with any of the following criteria may not enroll in the study:

• Subject has non-migraine headache, retinal migraine, basilar or hemiplegic migraine, cluster headache, or headaches secondary to trauma, cranial or cervical disorders, infections, alterations of homeostasis, ENT disorders, psychiatric disorders or cranial neuralgias.
• Subject has confirmed or suspected ischemic heart disease (angina pectoris, history of myocardial infarction, documented silent ischemia), Prinzmetal's angina/coronary vasospasm, or signs/symptoms consistent with any of the above.
• Subject has evidence or history of ischemic abdominal syndromes, peripheral vascular disease or Raynaud's Syndrome.
• Subject has cardiac arrhythmias requiring medication or a history of a clinically significant electrocardiogram abnormality that, in the investigator's opinion, contraindicates participation in this study.
• Subject has a history of cerebrovascular pathology including stroke and/or transient ischemic attacks (TIAs).
• Subject has a history of congenital heart disease.
• Subject has uncontrolled hypertension at screening (sitting systolic pressure ≥140mmHg, diastolic pressure ≥90mmHg).
• Subject, 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, strong family history of coronary artery disease, female with surgical or physiological menopause, or male over 40 years of age).
• Subject has a history of epilepsy or structural brain lesions which lower the convulsive threshold or treated with an antiepileptic drug for seizure control within 5 years prior to screening.
• Subject has a history of impaired hepatic or renal function that, in the investigator's opinion, contraindicates participation in this study.
• Subject is currently taking a monoamine oxidase inhibitor (MAOI), or has taken a MAOI within 2 weeks prior to screening or plans to take within 2 weeks after treatment.
• Subject is currently taking, or has taken in the previous three months, a migraine prophylactic medication containing methysergide or dihydroergotamine; or is taking a medication that is not stabilized (i.e. change of dose within the past 2 months) for either chronic or intermittent migraine prophylaxis or for a co-morbid condition that is not stabilized..
• Subject is currently taking any anti-coagulant (e.g., warfarin).
• Subject has a recent history of regular use of opioids or barbiturates for treatment of their migraine headache and/or other non-migraine pain. Regular use is defined as an average of 4 days per month over the last 6 months.
• Subject is currently taking or has taken in the previous 4 weeks, herbal preparations containing St. John's Wort (Hypericum perforatum).
• Subject has hypersensitivity, intolerance, or contraindication to the use of sumatriptan or naproxen sodium or any of their components or any other 5-HT1 receptor agonist.
• Subject has a history of allergic reactions to naproxen preparations, including subject in whom aspirin or other NSAID drugs induce the syndrome of asthma, rhinitis, and nasal polyps.
• Subject has a history of any gastrointestinal surgery that specifically indicates a past history of bleeding, ulceration or perforation.
• Subject has a history of gastric bypass or stapling surgery.
• Subject has a history of GI ulceration in the past six months or gastrointestinal bleeding in the past year.
• Subject has a history of inflammatory bowel disease.
• Subject has a history of any bleeding disorder.
• Subject is taking any antiplatelet agent (except low-dose aspirin ≤ 325mg/day for cardioprotective reasons).
• Subject is taking any angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker.
• Subject is pregnant, actively trying to become pregnant or breast-feeding.
• Subject has evidence of alcohol or substance abuse within the last year which, in the investigator's judgment, will likely interfere with the study conduct, subject cooperation, or evaluation and interpretation of the study results.
• Subject has any concurrent medical or psychiatric condition which, in the investigator's opinion, may affect the interpretation of efficacy and safety data or which otherwise contraindicates participation in this clinical trial.
• Subject 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.