Amitriptyline to Prevent Headache After Traumatic Brain Injury

Research Hypothesis and Aims: The ultimate aim of this research is to determine whether early
treatment using amitriptyline can prevent the development of chronic headache after TBI. This
proposal is for preliminary work that will give some indication of the effect of
amitriptyline and provide information needed to design a definitive study of the efficacy of
amitriptyline for the prevention of chronic post-traumatic headache.

Specific Aim 1 is to conduct a two-arm open-label study to examine the effect of preventive
treatment with amitriptyline on the frequency and severity of headache after mild TBI
compared to that seen in our observational study on the natural history of headache after
mild TBI.

Specific Aim 2 is to collect data needed for design of a Phase III study, including an
estimate of effect size, the variability in the number of headache days in those with mild
TBI, and determining a desirable initiation date for preventive treatment (e.g., week 1 or
month 1 after injury).

Specific Aim 3 is to examine the feasibility of headache diary use in individuals with mild
TBI.

Specific Aim 4 is to establish the safety and tolerability of amitriptyline for the
prevention of headache after mild TBI.

Hypothesis: Preventive treatment of early headaches with amitriptyline after mild TBI results
in decreased prevalence of recurrent headache (percent of participants having at least 1
headache/week) and severe headaches (percent of participants having headaches with an average
pain of 5 or higher) at three months as compared to the frequency and severity of headache in
those followed in the natural history study who received usual care.

Data Collection and Measures: Data collection will occur at enrollment, at each clinic visit,
and at Day 180. An examiner blinded to group assignment will administer all measures at
Clinic Visit 1 as cognition will be compared between groups at that time point; other
assessment points will be unblinded.

Primary Outcome Measure: Frequency and severity of headaches at 90 days after study
initiation.

Secondary Measures: Secondary measures are the Brief Pain Inventory, Analog Pain Scale, Pain
Sites, Headache Impact Test-6 (HIT-6), Insomnia Severity Index (ISI), Patient Health
Questionnaire-9 (PHQ-9), General Anxiety Disorder - 7 Item Scale (GAD-7), Alcohol Use
Disorders Identification Test—Consumption (AUDIT-C), Rivermead Post-Concussion Symptom
Questionnaire (RPQ), EuroQol, Health Survey Short Form-12® (SF-12), and Satisfaction with
Life Scale. Caffeine use and drug use questions will be asked that will model the AUDIT
questions. Additional measures will be obtained at baseline to characterize injury type and
severity, medication use, and accompanying disorders.

Headache Diary: The subject will be asked to fill out a headache diary each day during the
study to rate the frequency and severity of headache as well as some simple headache
characterization.

Enrollment and Randomization: Informed consent will be obtained from the participant as
approved by the Human Subjects Division of the University of Washington. Subjects will be
randomized into one of two groups (Group 1: early start vs. Group 2: delayed start) using a
computerized blocked randomization, stratified on headache severity (average severity of <4
vs. >5).

Medication administration and dosing adjustments: The study drug, amitriptyline, will be
dispensed in medication containers clearly marked with the dosage and instructions to take at
bedtime daily (separate containers for 10 mg, 25 mg, and 50 mg). Once randomized, Group 1
participants will be started on one 10 mg capsule each evening. The dosage will be adjusted
upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3. Group 2 participants
will be assessed on Clinic Visit 1 (Day 30) for current headache. If the participant has
continued to have headaches (new or worse than pre-injury), he/she will have the same ramp-up
schedule when the study drug is started at Day 30. Those in group 2 who do not have headaches
at day 30 will be followed by phone and with headache diaries throughout the study including
outcomes. If the perceived side effects of the study drug are intolerable at any time during
the study, subjects will be asked to decrease the dosage to half a pill until a new
prescription arrives. If side effects remain intolerable after 3 days on the lower dose, that
subject will be discontinued from the study drug but followed in the study. Regardless of
dose, the schedule for visits and testing will continue. Participants will be allowed to use
rescue medications as needed for headache.

Compliance: Each dosage will be in a separate pill container and clearly marked. Compliance
will be assessed during the weekly telephone follow-up calls and at the follow-up clinic
visits. Pill counts will be performed at each visit. Adequate compliance will be considered
80% medication consumption.

Schedule of Visits: Baseline Hospital Visit. Measures administered will include an interim
medical history form (diagnoses, current medications), headache survey, pain measures, HIT-6,
PHQ-9, ISI, RPQ, and SF-12. After completion of baseline assessments, the research assistant
will instruct the participant in the use of a daily headache diary. The research assistant
will distribute the labeled study drug to each Group 1 participant and will instruct on use.
Participants will be given a schedule for increasing the dose weekly. Subjects will be asked
to keep their pill containers to turn in at the next clinic visit.

Telephone Follow-Up Calls 1-9 (between clinic visits). The research assistant will contact
the participant weekly (Telephone Follow-Up Calls 1, 2, 3) after enrollment to check on
completion of headache diary and to confirm frequency and severity of headaches during the
preceding week, study drug use, and use of rescue medications. In the case of adverse effects
which are bothersome to the patient (e.g., mild sedation, dry mouth, constipation), the
dosage will be decreased by one dosage level or by ½ pill per day.

Clinic Visit 1 (Day 30). For all participants on this visit, vital signs will be obtained.
Drug containers will be collected from Group 1 and headache diaries will be collected from
all subjects. Measures administered on this visit will include an interim medical history
form (new diagnoses, changes in medications), headache survey, pain measures, HIT-6, PHQ-9,
ISI, RPQ,and SF-12. Neuropsychological tests will be given on this visit only. For Group 1,
if the dosage was decreased secondary to minor adverse events in the interim, one of the
study physicians will meet with the participant to decide whether to maintain a lower dose or
have a second trial of returning to a higher dose of the study drug. The second month's
supply of study drug will be dispensed at this visit. For Group 2 participants with headache,
medications for the first month of treatment will be distributed along with a ramp-up
schedule.

Clinic Visit 2 (Day 60). Vital signs will be obtained. Drug containers and headache diaries
will be collected from all subjects. Measures administered on this visit will include an
interim medical history form (new diagnoses, changes in medications), headache survey, pain
measures, HIT-6, PHQ-9, ISI, RPQ, and SF-12. If the dosage was decreased secondary to minor
adverse events in the interim, one of the study physicians will meet with the participant to
decide whether to maintain a lower dose or have a second trial of returning to a higher dose
of the study drug. The final month's supply of study drug will be dispensed at this visit.

Clinic Visit 3 (Day 90). 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. Measures
administered on this visit will include an interim medical history form (new diagnoses,
changes in medications), headache survey, pain measures, HIT-6, PHQ-9, ISI, RPQ,and SF-12.

Telephone Follow-Up Call 10. The research assistant will call the subject at Day 180 to
administer the headache survey (which includes the HIT-6) and record current medications
only.

Subject Withdrawal: Subjects may be discontinued from the study drug on their request or if
the subject experiences an adverse effect sufficient to warrant withdrawal from the study
drug, In the case of discontinuation, the reason for withdrawal will be recorded and the
subject will be asked to continue to monitor their headaches with use of the headache diary.

Data Analysis Study Sample Size and Rationale: In a recent observational study, the
investigators observed that of people with new or worse headaches at baseline assessment
after mild TBI, 35% had 1 or more headaches per week at 3 months and a similar fraction had
average headache pain severity of 6 or more on a 0 (no pain) to 10 (worst pain imaginable)
scale. The study's two end points are: 1) reduction in the percent of people with baseline
headaches that has one or more headaches per week at 3 months; and 2) the reduction in the
percent of people with baseline headaches that experience headache severity of 6 or more on a
scale from 0 to 10 at 3 months. It will be necessary for 65 cases to be followed to 3 months
in order to have 80% power to reject the null hypothesis of a 35% headache rate if
amitriptyline taken as a preventive yields 21% of subjects having 1 or more headaches per
week (a 40% reduction in the percentage of people with frequent headaches at 3 months).
Similar numbers are needed to confirm a like reduction in the percent of participants with
severe headaches (average pain of 6 or greater). These are based on a 1-sided significance
level of 0.05. Allowing for up to 10% attrition (7 subjects), the investigators will recruit
and randomize 72 participants. Based on the previous natural history study, the investigators
expect about 104 cases per year to have new or worse headaches at baseline assessment. The
investigators expect 60% to meet the eligibility criteria and 60% of those to consent to
participate, yielding 37 cases per year to randomize.

Aim 1. The primary intent-to-treat analysis will determine the proportion of participants
with frequent (1 or more headaches per week) or severe (with average pain of 6 or higher)
headaches combining both arms at 3 months. Each of these proportions will be compared to the
rate of each recorded in our observational study using a normal approximation to the binomial
(one-sided chi-squared test). In the previous observational study, the investigators observed
35% with at least 1 headache per week and 36% with headaches having average pain of at least
6 on a scale from 0 to 10. A one-sided significance level of 0.05 will be used. The
investigators will also examine evidence for any differential benefit for amitriptyline
started at baseline or 1 month to help decide which to use for the Phase III trial if this
pilot suggests that is worthwhile.

Aim 2. Descriptive statistics will be used (means, standard deviations, proportions) to help
in the planning of the Phase II trial.

Aim 3 (feasibility of use of a headache diary). This will be addressed by examining the
number of participants who do not use their diary at all, have over 10% missing data, or who
report different values on the phone calls than is shown in the diary. Different modes of
completing the diary (paper, smart phone or web application) will be studied to see if any
are more user friendly for this population.

Aim 4. Descriptive statistics will be used to summarize the occurrence of adverse events. The
investigators will estimate the impact of amitriptyline on cognition by comparing the
neuropsychological performance at 1 month of those started on the drug at baseline to those
who start drug after the 1-month assessment. The mean difference on each test will be
calculated with a 95% confidence interval.

Inclusion Criteria:

- Acute mild TBI (Glasgow Coma Scale of 13-15 on emergency department evaluation, any
period of loss of consciousness (LOC) < than 30 minutes, alteration of consciousness
or post-traumatic amnesia (not to exceed 24 hours)

- Ability to give consent

- Ages 18-60

- Access to a telephone

- Current headache (new headache or headache worse than prior to injury)

Exclusion Criteria:

- Does not speak English

- Diagnosed seizure disorder

- Myocardial infarction in prior 6 months

- Cardiac arrhythmia requiring medication treatment

- Prolonged Q-T interval on electrocardiogram

- Psychosis

- Intoxication on hospital admission sufficient enough to cloud the diagnosis of mild
TBI

- Incarceration or homelessness

- Allergy to amitriptyline

- Current treatment with amitriptyline or other tricyclic antidepressant

- Currently taking any medication not recommended for use with amitriptyline due to the
potential for Q-T interval prolongation. Examples of this include: Class I, I-A or II
antiarrhythmics, TCA's, MAOI's, selected fluoroquinolones (gatifloxacin,
moxifloxacin), selected antipsychotic medications (haloperidol, risperidone,
quetiapine), selected antiretroviral medications, cisapride, chloroquine,
chlorpromazine, prochlorperazine, promethazine, citalopram, fluoxetine, erythromycin,
methadone

- History of glaucoma

- History of prostate disease or current urinary retention