Treximet in Acute Migraine Headache: Assessing Cognitive Function
Treximet in Acute Migraine Headache: Assessing Cognitive Function
Migraine headache occurs frequently in women more than men and is associated with symptoms
 not only of significant pain but also of symptoms typically including of photophobia,
 phonophobia, nausea and vomiting. Many migraine patients report difficulty in cognition from
 lack of concentration, difficulty in word finding or inability to remember. Many of these
 cognitive symptoms seem to be independent of the pain intensity and may occur completely
 separately from the headache pain but can be disabling. It is likely that the frequency and
 importance of cognitive symptoms associated with migraine are underreported.

 The Mental Efficacy Workload Test (MEWT) is a computerized battery that is designed to be an
 efficient and accurate measure of cognition during migraine headache. Treximet is a new
 migraine treatment recently FDA approved for the treatment for the relief of acute migraine
 that may be effective for the cognitive symptoms for migraine patients who have a history of
 cognitive dysfunction during a migraine headache. The primary efficacy parameter is to
 evaluate the effectiveness of treatment with Treximet versus placebo in patients with acute
 migraine headache measuring neuropsychological function using the MEWT during the migraine
 and comparing that score with a prior MEWT score when the patient had no migraine symptoms. A
 double blind, placebo-controlled, crossover study was chosen so that each patient may be her
 or his own control.

 It is the intent of this study to determine the type and intensity of cognitive dysfunction
 associated with migraine headache and to what extent that Treximet may relieve the cognitive
 dysfunction in a safe and effective manner.
Overall Study Design:

 This study is to be a double blind crossover comparison study in patients during a migraine
 headache attack, with assessments at one and two hours after treatment. Patients with an IHS
 diagnosis of migraine with or without aura may be included. The patients will complete a
 questionnaire regarding the nature of their migraine attacks, including their impression of
 cognitive impairment if any. Historically associated symptoms will be listed. Menstrual
 associated migraine history will be assessed. 30 patients will be randomized to Treximet or
 placebo in a 1:1 manner for the first treatment and in reverse order for treatment on the
 second migraine attack. In this manner, each patient will be his or her own control. 60
 migraine headaches will be treated in this study. Also, it has been previously discussed that
 after 3 practice sessions with the MEWT, further administration of the MEWT does not produce
 bias by a practice effect as the ANAM has been shown not to produce bias by a practice
 effect.10 Therefore, patients will have 3 practice sessions in the clinic before taking the
 baseline MEWT.

 During the baseline period, while the patient is without any migraine symptoms and feeling
 well (interictal period), three practice trials on the MEWT will be performed and a fourth
 MEWT trial will be taken with the score recorded for a neuropsychological baseline. When the
 patient experiences a migraine headache, the patient will rate headache severity and
 associated symptoms and then take Treximet or matching placebo. The patient will repeat
 headache and associated symptom checklist and the MEWT at 1 and 2 hours after treatment.
 Rescue medication will be allowed at 2 hours for those patients who require it.

 4.0 Clinical Methods:

 4.1 Selection of Study Population:

 4.2 Visit 1 (Screen visit): After informed consent reviewed and signed, inclusion and
 exclusion criteria reviewed and the patient approved for the study, patients will have
 assessments and practice MEWT sessions as listed below. The patients will then be scheduled
 for visit 2 .

 These assessments will be completed in the following order:

 1. . Type(s) of migraine including menstrual migraine

 2. . Medical and surgical history

 3. . Migraine history: age of onset, age of onset of cognitive dysfunction

 4. . Family history of migraine

 5. . Prior treatment for migraine, both rescue and preventative

 6. . Age, sex, educational background

 7. Concomitant medications

 8. General physical and neurological examinations

 9. Reviewing with patient headache severity and symptom assessment forms

 10. Two practice sessions on the MEWT

 4.3 Visit 2 Patient is to return to clinic within 2 weeks to review headache severity
 and symptom forms to be filled out at home or work while experiencing a migraine. Two
 MEWT sessions will be taken, one last session for practice and the other for a baseline
 test to be compared to MEWT assessment while experiencing a migraine. Subject is
 randomized to treximet or placebo and given medication package and instructions .*
 Subject is also given MEWT device to take home along with assessments and diary.

 4.4 Visit 3 (Post-treatment visit #1): The patient is to return to the clinic within one
 week of treating a migraine to review headache severity and symptom assessment forms,
 MEWT scoring and adverse event (AE) dairy. Patient given second medication package for
 second migraine treatment.* Subject given MEWT device and assessment forms to take home
 and complete when experiencing headache.

 4.5 Visit 4 (Post-treatment visit #2): The patient is to return to the clinic within one
 week of treating the second migraine to review headache severity and symptom assessment
 forms, MEWT scoring and AD dairy.

 * Patients may take rescue medication of choice after 2 hours of taking Treximet or
 placebo if they wish.

 5.0 Adverse Events

 An adverse event definition for this protocol is as follows:

 Any unexpected, untoward medical occurrence that is considered clinically significant by
 the investigator.

 All adverse events fitting this description will be captured and recorded on the case
 report forms.

 In the event that a subject is withdrawn from the study because of an adverse event, it
 must be recorded on the CRF as such. The subject should be followed and treated by the
 investigator until the abnormal parameter or symptom has resolved or stabilized.

 All adverse events will be recorded in the Case Report Form (CRF)

 6.0 Serious Adverse Events

 A serious AE means any adverse event fitting the description above but also containing
 one of the following:

 -  Death

 -  Life threatening experience which places the subject at immediate risk of death
 from the event as it occurred.

 -  Full Inpatient hospitalization or prolongation of hospitalization

 -  Persistent or significant disability/incapacity

 -  Congenital anomaly or birth defect

 Any reports of these events during the conduct of the study will immediately be reported
 to the sponsor, to the IRB and to Medwatch.

 7.0 Statistical analysis plan, sample size justification and power analysis

 Cognitive function and efficacy analysis (pain relief) will be calculated on the
 intent-to-treat (ITT) population. Statistics will be presented for headache response
 (0-3 scale), pain-free response, safety and demographics. Five subsets of MEWT will be
 used (CPT, MTS, MP, PRT and SRT -see Table 1). Four of the subset tests of the MEWT
 (CPT, MTS, MP, and PRT) will be scored for 'throughput,' which is the number of correct
 responses per minute. This is a measure of efficacy that combines both speed and
 accuracy in a single score. SRT will be calculated for reaction time in msec. Group
 means will be calculated from each patient's mean for each MEWT subtest and compared to
 each stage of the migraine: migraine-free, migraine pre-treatment (time zero) and
 migraine post-treatment (time 1 and 2 hours). Each MEWT subtest will be calculated using
 a repeated measure 1 x 3 (each stage of migraine: migraine free, pre and post-treatment)
 by analysis of variance (ANOVA) for statistical significance of at least p = 0.05 or
 better.

 8.0 Duration of study

 Nine months (30 patients with baseline practice sessions, treatment of 2 separate
 migraine headaches)

 9.0 Specific drug supply requirements

 Treximet and matching placebo

 10.0 Publication/presentation plan

 Submission to a national and/or international headache meeting as soon as the data have
 been analyzed. Submission to a peer review journal within 6 months of study analysis
 completion.

 11.0 Source Documentation and Case Report Form Completion

 Source documents are defined as original documents, data and records. These may include
 hospital records, clinical and office charts, lab results, cognitive data and
 information, etc. The Case Report Form documents will serve as the source records for
 this trial. All forms will be completed within 5 business days of the study visit. A CRF
 will be provided for each enrolled study subject. All CRFs will be completed using black
 ink. All corrections will be made by striking through with a single line and writing
 correct data above, beside, or below the erroneous data, so as not to obscure the
 original entry. Each correction will be initialed and dated by the person making the
 correction.

 12.0 Retention and Availability of Records

 The investigator will maintain adequate records for the protocol including signed
 Informed consents, patient information sheets, completed source documents, CRF's, Lab
 reports, Medical records, AE reports and information regarding all subjects who
 discontinued.

 13.0 Ethics

 Good Clinical Practice (GCP) requires that the clinical protocol, any protocol
 amendments, the Investigators Brochure if applicable, informed consent/assent, and all
 other forms of subject information related to the study (including advertisements) be
 reviewed by the IEC/IRB. IRB approval is mandatory before initiating of any study
 related activities.

 The study will be conducted per the protocol, in accordance with ICH guidelines,
 applicable regulations, and guidelines governing clinical study conduct and the ethical
 principles that have their origin in the Declaration of Helsinki.

 14.0 Use of Information/Confidentiality

 All information obtained during the conduct of this clinical trial is considered
 confidential. This information may be disclosed as deemed necessary by Neurological
 Research Center Inc or GlaxoSmithKline, Inc. to other clinical investigators, the
 IEC/IRB, the FDA and other governmental agencies. Patient identifiers will include
 patient assigned number, age, and sex. Patient Initials will not be released to the
 company as this is irrelevant information. The investigator will maintain a confidential
 subject identification code list of all subjects enrolled in the study by name and
 subject number. This list will be maintained at the investigative site.
Inclusion Criteria:

 1. Females and male subjects, ages 18-65 inclusive

 2. Have migraines with or without aura as expressed by the International Headache Society
 (IHS) criteria for at least six months and at least one attack per month for three
 months prior to screening

 3. If female, have an acceptable method of contraception during the study, have no plans
 to become pregnant and have a negative urine pregnancy test at screening and
 throughout the study.

 4. Must be able to follow study protocol including all neuropsychological testing, MEWT
 assessments and evaluation forms.

 5. Must be willing and able to provide written informed consent

 Exclusion Criteria:

 1. Have more than 15 headache days per month

 2. Have hemiplegic or secondary headaches

 3. Have significant risk factors for cardiovascular or cerebrovascular disease as
 assessed by the investigator

 4. Are taking any medication that is contraindicated with a triptan or NSAIDs

 5. Have any significant concomitant disease

 6. Have any allergy to triptans, aspirin or NSAIDs

 7. Have a history of substance abuse, psychiatric illness in the last 5 years

 8. Are participating or have participated in an investigational drug trial within the
 last 30 days