Sumatriptan as Treatment for Post-traumatic Headache

I. Specific Aims of Study: The ultimate aim of this Phase II open-label study is to test the
research methods and approach necessary to successfully carry out a Phase III study for the
treatment of post-traumatic headache (PTH). During this study, we will

1. Determine the feasibility of using a headache diary accessed via smart phone
application, the web, or paper/pencil to record accurate headache data in a group of
individuals with TBI, and their caregivers as indicated.

2. Evaluate the approximate effect size of sumatriptan on pain severity, duration, and
recurrence of headaches in persons with moderate to severe PTH in order to establish the
necessary sample size for a Phase III study.

3. Assess the side effect profile of sumatriptan in a brain-injured population as well as
the safety of sumatriptan in subjects with TBI.

4. Evaluate the ability of persons with TBI, and their caregivers as indicated, to
successfully use abortive headache medications and comply with treatment.

5. Examine the relationship between PTH and cognitive, emotional, and other self-report
measures to determine important factors to include in a Phase III study.

This is a single arm, unblinded study enrolling 40 subjects and is being undertaken to test
necessary study instruments and procedures, establish feasibility and determine side effects
in a population with mild complicated, moderate or severe TBI in preparation for a subsequent
Phase III study.

Data collection will occur at enrollment (Clinic Visit 1) at which baseline testing will
occur, Day 30 (Clinic Visit 2), and Day 90 (Clinic Visit 3).

Pre-treatment Visit (Visit 1): Subjects who complete informed consent and meet the inclusion
criteria (with no exclusion criteria) will be asked to complete 30 days of headache diary to
document the number of headaches, headache severity, headache days and description of their
headache and associated symptoms. Research staff will contact them on a weekly basis to
answer questions and maximize accuracy and compliance with the diary. Proper utilization of a
headache diary and success of data input by the subject and caregiver will be evaluated
following weekly interviews with the research assistant.

Treatment Visit (Clinic Visit 2):

A medical history will be obtained to review inclusion and exclusion criteria and to elicit a
thorough review of systems so that adverse events will be identifiable if they occur.
Physical examination will also ensure that cardiovascular status is compatible with
sumatriptan use and will document current status to allow for identification of potential
adverse events. Finally, standard primary headache classification criteria will be reviewed
with each patient to determine whether they meet criteria for migraine or probable migraine.
Headache histories will be assessed and subjects that have experienced between 4-15 headaches
will be included in the medication intervention with Sumatriptan. Subjects who qualify for
the Sumatriptan intervention will receive several assessments, given medication, usage
instructions, and scheduled for weekly phone calls for weeks 5-11. Individuals whose
headaches do not meet criteria for migraine or probable migraine, based on data from headache
diaries, will have their participation in the study end.

Weekly Telephone Follow-Up Calls: Research staff will call each participant weekly to check
on compliance with drug diary use during the first month of the study (Weekly calls 1-3) to
check on compliance in diary usage. For weekly calls in weeks 5-11 (for the intervention
participants), research staff will inquire about study drug usage, and query for adverse
events. Use of rescue medications for headache will be recorded. In the case of minor adverse
effects which are bothersome to the patient, the dosage will be decreased by ½ pill per use.

Follow up Visit (Visit 3). This will be the final visit for the subjects. Vital signs will be
obtained. Drug containers and headache diaries will be collected from all subjects. Outcome
measures will be administered.

Use of sumatriptan and rescue drug: Two packages of nine (9) sumatriptan 100- mg. pills (18
pills total for 2 months of treatment) will be dispensed to each subject on Day 30 once they
have gone through baseline assessment. On average, this will treat a minimum of 5 headaches
or a maximum of 9 headaches per month. Subjects will be instructed to take the sumatriptan at
the onset of headache pain. If subjects are not pain free at 2 hours after the first dose of
study medication, they will be allowed to take one additional pill, but will be limited to 2
pills in a 24 hour period. Subjects will be instructed to take no more than 9 pills in a 30
day period based on research which suggests that additional dosages may increase the risk of
medication-overuse headache. A list of appropriate medications will be provided that they can
use if they: 1) continue to have headache pain 2 hours after their second dose of study drug,
or 2) they have used their 30 day supply of study drug within the month. All subjects will be
contacted by telephone on a weekly basis to review their headache diaries, assess potential
adverse events, review compliance with use of the study drug, assess other treatments being
utilized, and answer any questions.

Data Analysis: Data analysis for the feasibility and safety aims will be primarily
descriptive. The investigators will calculate the percent of subjects who used the diary
successfully, percent who stopped taking sumatriptan because of side effects, percent who
experienced each adverse event, and percent who were able to maintain compliance with
treatment. A confidence interval will be determined for each estimate. To get preliminary
data on efficacy of sumatriptan, headache control will be compared before and after the
participants start taking sumatriptan. The investigators will calculate the percent of
headaches that had complete resolution (pain free at 2 hours) for each person, during the
initial (pre-intervention) month when they used their regular treatment and during the two
months (intervention) when they treated headaches with sumatriptan and compare them using a
paired t-test. The investigators will also examine different definitions of headache relief
(pain free by 30 minutes, no more than mild pain (score <=1) by 30 minutes, no more than mild
pain by 2 hours) to see if another outcome measure may have advantages for a future Phase III
study. Any differences in compliance, side effects, and feasibility based on cognitive
functioning will be described, as well as by other self-report and emotional health measures.
Changes in these measures from pre to post treatment will also be examined to determine
whether there is any change that occurs with treatment and which may be important variables
to include in a Phase III study.

Inclusion Criteria:

- Age 18-65. The lower age limit is set for ability to consent as an adult for research
participation as well as being a minimum age for administration of most validated
outcome measurements. The higher age limit is set to 65 to reduce likelihood of health
issues which may be a contraindication to the use of sumatriptan and to meet
recommendations by the International Headache Society.62

- Diagnosis of TBI occurring at least 3 months but not greater than 60 months before
enrollment. Three months was chosen to include only those subjects who are having
headache beyond their acute injury and 60 months to identify the ability of
individuals with TBI and headache to use both a headache diary and the medication.

- Subject has at least four and up to a maximum of fifteen total headache days per
month. Subject report of meeting this criteria will result in the subject entering the
first month of the study. However, this frequency must be documented in headache diary
to enter the treatment phase of the study.

- Headaches are classified as moderate to severe (2 or 3 on the 4 point pain scale: 0=no
headache, 1=mild headache, 2=moderate headache, 3=severe headache). As above, headache
severity must be documented in the month-long headache diary prior to entry into the
treatment phase.

- Subject is able and willing to give written informed consent for participation in
screening activities and to participate fully in the study if eligible. For those
subjects who score below 25 on the Mini Mental Status Examination, there must be a
caregiver willing to also be consented for participation in the study.

- Female subjects of childbearing potential must have a negative pregnancy test at
enrollment, and agree to remain abstinent or use acceptable methods of birth control
(i.e., hormonal contraceptives, intrauterine device, diaphragm with spermicide,
cervical cap or sponge, condoms, or partner has had a vasectomy). Sumatriptan has been
assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of
decreased fetal body weight, embryo lethality, and cervicothoracic vascular defects.
There are no controlled data in human pregnancy and therefore, sumatriptan should only
be given during pregnancy when benefit outweighs risk.

Exclusion Criteria:

- History of ischemic heart disease (angina pectoris, history of myocardial infarction,
silent ischemia, Prinzmetal's angina/coronary vasospasm, ischemic bowel disease, or
peripheral vascular disease) based on self-report or history of basilar or hemiplegic
migraine.

- Uncontrolled hypertension at initial visit (sitting systolic pressure > 140 mm Hg,
diastolic pressure > 90 mm Hg).

- Impaired renal or liver function by medical history.

- Subject has taken an MAO inhibitor within 2 weeks of screening because these drugs and
sumatriptan use the same metabolic pathway.

- Subject has hypersensitivity reactions or other intolerance to sumatriptan or any
other 5-HT 1B/1D-receptor agonists.

- If subjects have medication overuse headache in the opinion of the investigator (if
using medication to treat acute headache on more than 15 days per month).

- Inability to speak or read English which would limit ability to interact with
examiners and complete headache diary and other questionnaires during this study.