Sumatriptan as Treatment for Post-traumatic Headache
Sumatriptan as Treatment for Post-traumatic Headache
This phase II evaluation of sumatriptan as a treatment for post traumatic headache (PTH) will
 examine the methods and approach necessary to take the next step to a phase III trial. The
 sample will include 40 persons with mild complicated, moderate or severe TBI who will be
 recruited from patients discharged from the acute rehabilitation unit as well as outpatient
 clinics and the community who are between 3 and 24 months of injury and will be followed over
 3 months. The investigators plan to enroll those who have moderate to severe headache with
 frequency of at least four and up to a maximum of fifteen total headache days per month and
 at least three months after discharge from hospital. The investigators will use headache
 diaries to track the headaches for a month. If subjects still have significant headache, the
 investigators will instruct them in the use of sumatriptan 100 mg. to treat headaches. The
 subjects will continue to keep daily headache diaries. The investigators will evaluate them
 at baseline, Day 30 and Day 90. Each subject will receive weekly telephone follow up calls
 from the research staff. The investigators will measure pain severity, duration, recurrence
 of headaches, and side effects and how well persons with TBI can use headache diaries.
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.