Amitriptyline to Prevent Headache After Traumatic Brain Injury
Amitriptyline to Prevent Headache After Traumatic Brain Injury
The investigators propose to conduct a 2-arm, open-label pilot study to determine if early
 treatment with amitriptyline will decrease the frequency and severity of headaches after mild
 traumatic brain injury (TBI). Amitriptyline is a tricyclic antidepressant that is commonly
 available and inexpensive. It is used as a first-line drug for primary headache prevention in
 a very low dose range of 10-50 mg.

 -  Specific Aim 1 is to conduct a 2-arm open-label study to examine the effect of
 preventive treatment with amitriptyline on the frequency and severity of headache after
 mild TBI.

 -  Specific Aim 2 is to collect data needed for design of a Phase 3 study, including an
 estimate of effect size, headache variability, and desirable drug treatment start date.

 -  Specific Aim 3 is to examine the feasibility of using headache diaries with individuals
 with mild TBI.

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

 The investigators hypothesize that early preventive treatment with amitriptyline will avert
 the development of chronic post-traumatic headache (PTH) as compared to rates of headache
 from a recent natural history study on PTH after mild TBI.

 The investigators propose to enroll inpatient subjects from a Level I trauma center as well
 as from outpatient clinics and from the general community with a diagnosis of mild TBI.
 Subjects will be screened for current headache. After baseline assessment, 72 subjects with
 current headache will be randomized to one of 2 groups. Group 1 will immediately begin
 amitriptyline and or Group 2 will be followed and begin amitriptyline at Day 30. All subjects
 will be asked to complete a daily headache diary beginning on Day 1 of the study. A detailed
 medical history and headache survey will be completed. Subjects will have a scheduled stepped
 increase in the drug dosage every week for 3 weeks to the maximum study dosage of 50 mg.
 Weekly telephone calls will monitor for adverse events and compliance with the drug and
 headache diary. Clinic visits will occur at 30, 60 and 90 days. The 30 day clinic visit will
 include cognitive testing to assess for differences between groups and initiation of drug
 treatment for Group 2. Both 30 and 60 day visits will include review of headache diary,
 potential adverse effects, and pill counts. The 90 day visit will be for outcome assessment.
 In addition, the headache survey will be repeated by telephone at Day 180.
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