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.