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

• Number of Participants With a Pain-free Response From 2 to 48 Hours Post-dose [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Pain-Free is defined as having no pain and without the use of any rescue medication from the time of the initial dose of study medication for a particular migraine attack until the defined time point at 2, 4, 6, 8, 24 or 48 hours post-dose.
• Number of Participants Using Rescue Medication Within 48 Hours Post Dose [ Time Frame: From dose time through 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Number of participants who took any medication to treat their migraine pain or symptoms within 48 hours after they took the first dose of study medication (placebo, Treximet, or butalbital-containing combination medication) for that attack. Participants were asked not to take rescue for at least 2 hours after they took the study medication (placebo, Treximet, or butalbital-containing combination medication) for that attack. Participants took rescue medication if they felt they needed it.
• Mean Time to First Use of Rescue Medication for the First Attack Treated With Study Medication (Attack 1) [ Time Frame: From dose time through 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Average time until participants took any medication to treat their migraine pain or symptoms within 48 hours after they took the first dose of study medication (placebo, Treximet, or butalbital-containing combination medication) for the first migraine attack treated. Participants were asked not to take rescue for at least 2 hours after they took the study medication (placebo, Treximet, or butalbital-containing combination medication) for that attack. Participants took rescue medication if they felt they needed it.
• Mean Time to First Use of Rescue Medication for the Second Attack Treated With Study Medication (Attack 2) [ Time Frame: From dose time through 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Average time until participants took any medication to treat their migraine pain or symptoms within 48 hours after they took the first dose of study medication (placebo, Treximet, or butalbital-containing combination medication) for their second migraine attack treated in the study. Participants were asked not to take rescue for at least 2 hours after they took the study medication (placebo, Treximet, or butalbital-containing combination medication) for that attack. Participants took rescue medication if they felt they needed it.
• Mean Time to First Use of Rescue Medication for the Third Attack Treated With Study Medication (Attack 3) [ Time Frame: From dose time through 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Average time until participants took any medication to treat their migraine pain or symptoms within 48 hours after they took the first dose of study medication (placebo, Treximet, or butalbital-containing combination medication) for their third migraine attack treated in the study. Participants were asked not to take rescue for at least 2 hours after they took the study medication (placebo, Treximet, or butalbital-containing combination medication) for that attack. Participants took rescue medication if they felt they needed it.
• Number of Participants With a Migraine-free Response 2-48 Hours After Dosing [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Migraine-free is defined as pain-free with no migraine-associated symptoms (nausea, vomiting, photophobia [sensitivity to light], and phonophobia [sensitivity to sound]) with use of any rescue medication before the defined time point.
• Number of Participants With Pain-freedom and Relief of Nausea at 2, 4, 6, 8, 24 and 48 Post-dose Time Points [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The number of participants with no pain and relief of nausea in those participants for whom nausea was present at dose time. Participants using rescue medication were removed from the participants with relief group for all subsequent timed assessments, regardless of pain and associated symptom evaluations at the specified time point.
• Number of Participants With Pain-freedom and Relief of Photophobia at 2, 4, 6, 8, 24 and 48 Post-dose Time Points [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The number of participants with no pain and relief of photophobia in those participants for whom photophobia was present at dose time. Participants using rescue medication were removed from the participants with relief group for all subsequent timed assessments, regardless of pain and associated symptom evaluations at the specified time point.
• Number of Participants With Pain-freedom and Relief of Phonophobia at 2, 4, 6, 8, 24 and 48 Post-dose Time Points [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The number of participants with no pain and relief of phonophobia in those participants for whom phonophobia was present at dose time. Participants using rescue medication were removed from the participants with relief group for all subsequent timed assessments, regardless of pain and associated symptom evaluations at the specified time point.
• Number of Participants With Pain-freedom and Relief of Vomiting at 2, 4, 6, 8, 24 and 48 Hours Post-dose [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The number of participants with no pain and relief of vomiting in those participants for whom vomiting was present at dose time. Participants using rescue medication were removed from the participants with relief group for all subsequent timed assessments, regardless of pain and associated symptom evaluations at the specified time point.
• Number of Participants With Relief From Sinus/Facial Pain at 2, 4, 6, 8, 24 and 48 Hours After Dosing in Those Who Also Had the Symptom at Dosing [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The number of participants with no pain and relief of sinus/facial pain in those participants for whom sinus/facial pain was present at dose time. Participants using rescue medication were removed from the participants with relief group for all subsequent timed assessments, regardless of pain and associated symptom evaluations at the specified time point.
• Number of Participants With Relief From Neck Pain at 2, 4, 6, 8, 24 and 48 Hours After Dosing Who Also Had the Symptom at Baseline [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The number of participants with no pain and relief of neck pain in those participants for whom neck pain was present at dose time. Participants using rescue medication were removed from the participants with relief group for all subsequent timed assessments, regardless of pain and associated symptom evaluations at the specified time point.
• Number of Participants With Pain Relief at 2, 4, 6, 8, 24 and 48 Hours After Dosing Moderate or Severe Baseline Pain [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Pain relief is defined as having no or mild pain and no use of rescue medication after dosing in those participants who had moderate or severe pain at dosing.
• Number of Participants Who Reported a Complete Symptom-Free Response at 2, 4, 6, 8, 24 and 48 Hours After Dosing [ Time Frame: At 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Complete symptom-free is defined as migraine-free, neck pain-free, and sinus pain-free without the use of any rescue medication prior to the defined time point.
• Mean Performance Index (PI) Scores at Time of Dosing and at 2, 4, 6, 8, 24 and 48 Hours After Dosing [ Time Frame: At time of dosing, and at 2, 4, 6, 8, 24, and 48 hours post-dose for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Overall cognition was assessed with a composite score (range 0-9) called the Performance Index, as derived from the number of correct responses per minute on subtests of the Mental Efficiency Workload Test (MEWT) cognitive battery. For a particular participant, lower scores indicate a negative impact, or worsened, general cognition; higher scores indicate improved cognition.
• Mean Stanford Sleepiness (SS) Scale Scores at Time of Dosing and at 2, 4, 6, 8, 24 and 48 Hours After Dosing [ Time Frame: Dose time, 2, 4, 6, 8, 24 and 48 hours post-dose. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Participant alertness was evaluated with the 7-point modified SS scale, where 1 is "feeling active, vital, alert, wide awake", 2 is "still functioning at high levels, but not peak; able to concentrate", 3 is "awake, but relaxed; responsive but not fully alert", 4 is "somewhat foggy, let down", 5 is "foggy, losing interest in remaining awake", 6 is "sleepy, woozy, fighting sleep, prefer to lie down", and 7 is "no longer fighting sleep, sleep onset soon, having dream like thoughts".
• Efficacy Subscore as Measured by the Revised Patient Perception of Migraine (PPMQ-R) Questionnaire 24 Hours After Treating a Migraine [ Time Frame: At 24 hours after dosing for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The PPMQ-R questionnaire was used to assess participant satisfaction with migraine medication; the answers are used to generate a total score and 4 subscales scores for efficacy, functionality, ease-of-use and bothersomeness-of-side effects. The total score was calculated as the average of the efficacy, functionality and ease-of-use subscores. Subscores could range from 0 to 100; higher scores indicate greater satisfaction.
• Functionality Subscore as Measured by the Revised Patient Perception of Migraine (PPMQ-R) Questionnaire 24 Hours After Taking Study Medication [ Time Frame: At 24 hours after dosing for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The PPMQ-R questionnaire was used to assess participant satisfaction with migraine medication; the answers are used to generate a total score and 4 subscales scores for efficacy, functionality, ease-of-use and bothersomeness-of-side effects. The total score was calculated as the average of the efficacy, functionality and ease-of-use subscores. Subscores could range from 0 to 100; higher scores indicate greater satisfaction.
• Ease-of-Use Subscore as Measured by the Revised Patient Perception of Migraine (PPMQ-R) Questionnaire 24 Hours After Taking Study Medication [ Time Frame: At 24 hours after dosing for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The PPMQ-R questionnaire was used to assess participant satisfaction with migraine medication; the answers are used to generate a total score and 4 subscales scores for efficacy, functionality, ease-of-use and bothersomeness-of-side effects. The total score was calculated as the average of the efficacy, functionality and ease-of-use subscores. Subscores could range from 0 to 100; higher scores indicate greater satisfaction.
• Bothersomeness-of-side Effect Subscore as Measured by the Revised Patient Perception of Migraine (PPMQ-R) Questionnaire 24 Hours After Taking Study Medication [ Time Frame: At 24 hours after dosing for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The PPMQ-R questionnaire was used to assess participant satisfaction with migraine medication; the answers are used to generate a total score and 4 subscales scores for efficacy, functionality, ease-of-use and bothersomeness-of-side effects. The total score was calculated as the average of the efficacy, functionality and ease-of-use subscores. Subscores could range from 0 to 100; higher scores indicate greater satisfaction.
• Total PPMQ-R Score as Measured With the Revised Patient Perception of Migraine (PPMQ-R) Questionnaire 24 Hours After Taking Study Medication [ Time Frame: At 24 hours after dosing for each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  The PPMQ-R questionnaire was used to assess participant satisfaction with migraine medication; the answers are used to generate a total score and 4 subscales scores for efficacy, functionality, ease-of-use and bothersomeness-of-side effects. The total score was calculated as the average of the efficacy, functionality and ease-of-use subscores. Subscores could range from 0 to 100; higher scores indicate greater satisfaction.
• Numbers of Participants Able to "Engage in Normal Activities Not Impaired" at Time of Dosing and 2, 4, 6, and 8 Hours After Dosing as Assessed by the CDQ (Clinical Disability Questionnaire) [ Time Frame: At dosing and at 2, 4, 6 and 8 hours after dosing of each attack treated with study medication. All 3 migraine attacks were to have been treated within 19 weeks of randomization (when study medication was dispensed). ] [ Designated as safety issue: No ]
  Clinical disability for each participant was assessed using the CDQ. This scale uses one question to assess ability to perform normal or usual activities. Responses are recorded on a 5-point scale, where 1 is "normal/not impaired", 2 is "mildly impaired", 3 is "moderately impaired", 4 is "severely impaired", and 5 is '"required bedrest".

• Subjects who are pain-free (PF) at 2 hours post-treatment [ Time Frame: 2-48 hours ] [ Designated as safety issue: Yes ]
• Effects on cognition of treating with BCM vs TREXIMA (as measured by the Mental Efficiency Workload Test (MEWT), measured at 2, 4, 6, 8, 24, and 48 hours [ Time Frame: 2-48 hours ] [ Designated as safety issue: Yes ]
• Subjects who use rescue medi [ Time Frame: 2-48 hours ] [ Designated as safety issue: Yes ]

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.

• Migraine Disorders
• Migraine, Acute

• Drug: TREXIMET®
  Sumatriptan + Naproxen Sodium (fixed dose combination tablet of sumatriptan succinate [equivalent to sumatriptan 85mg] and naproxen sodium 500mg)
• Drug: Butalbital-containing Combination Medications (BCM)
  butalbital-containing combination medication (BCM; acetaminophen 325mg, caffeine 40mg, and butalbital 50mg) [currently marketed as Fioricet]
• Drug: placebo
  placebo

• TPB
  TREXIMET® (Attack 1), placebo (Attack 2), BCM (Attack 3)
  Interventions:

  • Drug: TREXIMET®
  • Drug: Butalbital-containing Combination Medications (BCM)
  • Drug: placebo
• TBP
  TREXIMET® (Attack 1), BCM (Attack 2), placebo (Attack 3)
  Interventions:

  • Drug: TREXIMET®
  • Drug: Butalbital-containing Combination Medications (BCM)
  • Drug: placebo
• BTP
  BCM (Attack 1), TREXIMET® (Attack 2), placebo (Attack 3)
  Interventions:

  • Drug: TREXIMET®
  • Drug: Butalbital-containing Combination Medications (BCM)
  • Drug: placebo
• BPT
  BCM (Attack 1), placebo (Attack 2), TREXIMET® (Attack 3)
  Interventions:

  • Drug: TREXIMET®
  • Drug: Butalbital-containing Combination Medications (BCM)
  • Drug: placebo
• PTB
  placebo (Attack 1), TREXIMET® (Attack 2), BCM (Attack 3)
  Interventions:

  • Drug: TREXIMET®
  • Drug: Butalbital-containing Combination Medications (BCM)
  • Drug: placebo
• PBT
  placebo (Attack 1), BCM (Attack 2), TREXIMET® (Attack 3)
  Interventions:

  • Drug: TREXIMET®
  • Drug: Butalbital-containing Combination Medications (BCM)
  • Drug: placebo

• Silberstein SD, McCrory DC. Butalbital in the treatment of headache: history, pharmacology, and efficacy. Headache. 2001 Nov-Dec;41(10):953-67. Review.
• Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Transformed migraine and medication overuse in a tertiary headache centre--clinical characteristics and treatment outcomes. Cephalalgia. 2004 Jun;24(6):483-90.
• Wenzel RG, Sarvis CA. Do butalbital-containing products have a role in the management of migraine? Pharmacotherapy. 2002 Aug;22(8):1029-35. Review.
• Derosier F, Sheftell F, Silberstein S, Cady R, Ruoff G, Krishen A, Peykamian M. Sumatriptan-naproxen and butalbital: a double-blind, placebo-controlled crossover study. Headache. 2012 Apr;52(4):530-43. doi: 10.1111/j.1526-4610.2011.02039.x. Epub 2011 Nov 21.

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.