TREXIMET® Versus Butalbital-containing Combination Medications for the Acute Treatment of Migraine in Adults

A Randomized, Double-blind, Double-dummy, Placebo-controlled, Crossover Study to Evaluate the Efficacy of TREXIMET® (Sumatriptan + Naproxen Sodium) vs. Butalbital-containing Combination Medications for the Acute Treatment of Migraine When Administered During the Moderate-Severe Migraine Pain, Studies 1 and 2 of 2

Study TRX109011/TRX109013, A Randomized, Double-blind, Double-dummy, Placebo-controlled, Crossover Study to Evaluate the Efficacy of TREXIMET® (Sumatriptan + Naproxen Sodium) versus Butalbital-containing Combination Medications (BCM) for the Acute Treatment of Migraine when administered during the Moderate-Severe Pain Phase of the Migraine (Studies 1 and 2 of 2)

This study is a multicenter, randomized, double-blind, double-dummy, placebo-controlled, crossover, three-attack, outpatient study in which TREXIMET® will be compared to a butalbital-containing combination medication (BCM; acetaminophen 325mg, caffeine 40mg, and butalbital 50mg [Fioricet]) for the acute treatment of migraine headaches. Subjects will be randomized to one of 6 possible treatment sequences (TPB, TBP, BTP, BPT, PTB, PBT where T = TREXIMET®; P = Placebo; B = Butalbital-containing Combination Medication) . Subjects will treat each of the 3 migraine attacks when pain is moderate to severe. The study will include 4 visits: (1) a Screening visit at study entry, (2) a Drug Screen visit, (3) a Randomization visit, and (4) a Final visit. The Final visit occurs either (A) upon withdrawal or (B) after treatment of 3 migraine attacks. The primary objective is to evaluate the efficacy of TREXIMET® versus BCM for the acute treatment of moderate/severe migraine. These two replicate studies were amended while ongoing to allow for the reporting of pooled data only.

Inclusion Criteria:

• Males and females aged 18 to 65 years. Female subjects are eligible for participation if they are either of non-childbearing potential (not capable of becoming pregnant) OR of childbearing potential having a negative urine pregnancy test at screening, and using contraception if sexually active. If using oral contraceptives, the subjects should be on a stable regimen of oral contraceptives (>/= 2 months).

Eligible subjects must:

• have migraine with or without aura (2004 ICHD-II criteria) and must have had at least 2 attacks per month meeting these criteria in the three months prior to screening.
• have documented use of Butalbital-containing Combination Medication (MCM) to have treated at least one migraine.
• be able to understand how to complete the cognitive assessments and all other questionnaires programmed in an electronic diary.
• be willing and able to provide written informed consent.

Exclusion Criteria:

A subject is not eligible if they have:

• >8 migraines or >/= 15 headache days per month in total, or has retinal, basilar, or hemiplegic migraine, or secondary headaches.
• taken >350mg/day of butalbital and/or other barbiturates on an equivalent dose basis, on average, over the 30 days prior to screening.
• is likely to have unrecognized cardiovascular or cerebrovascular disease (based on history or risk factors).
• blood pressure >/= 140/90mmHg in 2 out of 3 BP measurements or is taking any angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker.
• history of congenital heart disease, cardiac arrhythmias requiring medication, or a clinical significant electrocardiogram abnormality.
• evidence or history of any ischemic vascular disease including: ischemic heart disease, ischemic abdominal syndromes, peripheral vascular disease or Raynaud's Syndrome, or signs/symptoms consistent with these.
• 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.
• a history of impaired hepatic or renal function that contraindicates participation in the study.
• hypersensitivity, allergy, intolerance, or contraindication to the use of any triptan, NSAID, aspirin, barbiturates, or acetaminophen (including all sumatriptan and naproxen preparations), has porphyria or has nasal polyps and asthma.
• is currently taking, or has taken in the previous three months, an ergot preparation for migraine prophylaxis; or is taking a migraine or prophylactic medication that is not stabilized (i.e. a change of dose within the last 2 months) for either chronic or intermittent migraine prophylaxis or for a co-morbid condition that is not stabilized.
• a recent history of regular use of opioids (including opioids in combination with butalbital, e.g. Fioricet with codeine) or barbiturates other than butalbital. Regular use is defined as an average of 4 days per month over the last 6 months.
• 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.
• history of any bleeding disorder or is currently taking any anti-coagulant or any antiplatelet agent (except low-dose aspirin </= 325mg/day for cardioprotective reasons).
• evidence or history of any gastrointestinal surgery or GI ulceration or perforation in the past six months, gastrointestinal bleeding in the past year; or evidence or history of inflammatory bowel disease.
• is pregnant, actively trying to become pregnant, breast feeding, or not willing to have pregnancy test performed.
• evidence of alcohol or substance abuse within the last year or any concurrent medical or psychiatric condition which, in the investigator's judgement, 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 study.
• participated in an investigational drug trial within the previous four weeks or plans to participate in another study at any time during this study.