Treximet in Acute Migraine Headache: Assessing Cognitive Function

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