Sumatriptan as Treatment for Moderate to Severe Post-Traumatic Headache
Phase: PHASE2
Conditions: Post-traumatic Headache
Sponsor: University of Washington

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TWIST: Treatment With Sumatriptan for TBI Headache 
(Sumatriptan as Treatment for Moderate to Severe Post-Traumatic Headache) 
 
Protocol Version 6.1 
Principal Investigator: Jeanne Hoffman, PhD 
 
Funded by National Institute on Disability, Independent Living and Rehabilitation Research 
H133A120028 
 
ClinicalTrials.gov Identifier: NCT01854385 
 
Investigators:  
Jeanne M. Hoffman, Ph.D. 
Sylvia Lucas, M.D., Ph.D. 
Sureyya S. Dikmen, Ph.D. 
Nancy Temkin, Ph.D. 
Jennifer Zumsteg, M.D. 
 
Natalia Murinova, M.D. – Data Safety Monitor 
 
Leslie Kempthorne, B.S. – Project Coordinator 
Jason Barber, M.S. – Systems Analyst 
Erica Wasmund – Research Assistant 
Taylor Obata, B.A. – Research Assistant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
 
 
 
 
 
 
Page Number 
Title/Investigators 
 
 
 
 
 
 
 
 
1 
 
Table of Contents 
 
 
 
 
 
 
 
 
2-3 
 
 
 
Need and Target Population 
 
 
 
 
 
 
4 
 
 
 
Beneficial Impact on the Target Population 
 
 
 
 
4-5 
 
 
Review of the Current Literature  
 
 
 
 
 
5 
 
 
 
Preliminary Data 
 
 
 
 
 
 
 
 
5-13 
 
Figure 1. Incidence and cumulative incidence of headache   
 
7 
Figure 2. Headache Impact by Frequency 
 
 
 
 
8 
 
Specific Aims of Study 
 
 
 
 
 
 
 
13 
 
 
 
Overview of Study Design   
 
 
 
 
 
 
14 
 
Table 1: Overview of Study Protocol  
 
 
 
 
15 
 
Population 
 
 
 
 
 
 
 
 
 
16-18 
 
 
Study Procedures 
 
 
 
 
 
 
 
 
19-24  
 
Recruitment 
 
 
 
 
 
 
 
 
19 
 
 
Data Collection and Measures 
 
 
 
 
 
19-22  
 
Table 2:  List of Measures 
 
 
 
 
 
 
20 
 
Enrollment and Schedule of Visits  
 
 
 
 
 
25-31  
 
 
Figure 3:  Summary of Participant Participation 
 
 
 
30 
 
Treatment with Sumatriptan Procedures  
 
` 
 
 
31-33 
 
 
 
Data Analysis 
 
 
 
 
 
 
 
 
33-35 
 
 
Data Management 
 
 
 
 
 
 
 
 
35- 37 
 
 
 
Plan of Evaluation 
 
 
 
 
 
 
 
 
37-38 
 
Objective and Quantifiable Performance Measures 
 
 
 
39 
 
 
Safety and Adverse Events  
 
 
 
 
 
 
39-47 
 
 
 
Ethical Considerations/Protection of Human Subjects 
 
 
 
47-49 
 
 

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Risk Assessment and Management  
 
 
 
 
 
50-52  
Potential Benefit of Study  
 
 
 
 
 
 
52 
 
 
 
Study Finances  
 
 
 
 
 
 
 
 
53 
 
 
Overall Project Evaluation  
 
 
 
 
 
 
53-54  
Table 4:  Performance measures 
 
 
 
 
 
 
55 
 
Project Staff  
 
 
 
 
 
 
 
 
 
 
 
Figure 4:  Project Staff 
 
 
 
 
 
 
56 
 
Timeline 
 
 
 
 
 
 
 
 
 
 
 
Table 5: Anticipated Timeline 
 
 
 
 
 
57 
 
 
References 
 
 
 
 
 
 
 
 
 
57-67  
 
 
 
 
 
 
 
 
 
 
 
Appendices 
 
Rescue Medications 
Headache Diary Questions 
Study Flowsheet 
Emergent Problem Protocol 
 
 
 
 
 
 
 
 
 
 

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I. 
 Need and Target Population: 
The Significance of the Problem of Headache after TBI: Since there are over 1 million people 
who sustain a TBI in the US each year1 and headache is one of the most frequent complaints 
after even mild TBI or concussion, PTH is an extremely common problem. Observational studies 
have demonstrated that the most common physical symptom following TBI in civilian and 
military groups is headache which is often persistent. Although some PTHs resolve soon after 
the initial injury, a substantial number of persons complain of headache that persists.21, 28, 29 In 
fact, our work in the last 5 years has indicated that approximately 70% of persons with TBI 
complain of headache in the year following their injury,19 though only about 17%  have had a 
prior history of headache before injury. 
Military figures also support the common occurrence of PTH. Almost 20% of Operation 
Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans are thought to have 
experienced a traumatic brain injury.3, 30 Headache stands out as the salient physical symptom 
that is specific to mild TBI where most other symptoms of TBI overlap with symptoms of post-
traumatic stress, acting as a marker of TBI.31 Headache is also a frequent residual symptom for 
those service members with moderate to severe TBI.21 For soldiers receiving care in a headache 
clinic after return from deployment, almost half met criteria for mild TBI.32  
II. 
Beneficial Impact on Target Population 
Why is treatment of PTH important? In general, beyond the work that we have conducted 
(see Figure 2 below), little research has been directed at the functional impact of chronic PTH. 
Cohen et al33 found that headache, including PTH, was a significant cause of unit attrition in 

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deployed military personnel, but did not specifically examine PTH separate from all other 
headache causes.  
III. 
Review of the Current Literature 
From the general headache literature, we know that chronic headache takes a major toll 
on productivity. Some investigations of quality of life in migraines  reveal significant adverse 
effects on the ability to participate in daily activities.34 In a random-dialing survey study, almost 
10% of people missed work because of a headache and 31% felt that their work effectiveness 
was reduced.35 Students report significant decreases in study productivity with the occurrence of 
headaches, migraine more so than tension-type.36 A 1999 study estimated that there was an 
economic cost of $13 billion a year in the U.S. for missed work days and decreased work 
productivity due to headache.37 A recent review article on disability in chronic daily headache 
notes that studies have documented a pervasive negative effect on work and household duties, as 
well as impairments in social and familial duties, cognitive functioning, and psychological 
health.22 We also know that painful conditions in general can result in sleep disturbance and 
depression, both of which can adversely affect cognition. It is likely that these effects would be 
at least as severe in persons after TBI who may be dealing with additional cognitive or 
behavioral challenges. For patients with TBI such functional impact may slow rehabilitation 
efforts and successful re-entry into employment and other areas of productive activity. 
 
IV. 
Preliminary Data 
Prior work on PTH at the UWTBIMS: In the prior cycle, we led a multicenter study, 
which prospectively followed a cohort of 452 persons enrolled into the TBI Model Systems at 7 

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centers over 16 months. Each subject was assessed in-person at baseline for current and 
persisting headache, headache history, headache characteristics, risk factors for headache 
occurrence, and effect of headache on normal function. Subjects were interviewed by research 
staff via telephone at 3, 6, and 12 months after injury with a headache survey including 
frequency, severity, and characteristics. 
The prevalence of PTH was high with over 40% of participants reporting headache at 
every time point measured (3, 6, and 12 months) after injury, indicating that PTH is a very 
common and persistent problem for those with brain injury. An astonishing cumulative 71% of 
the cohort reported PTH at some point during the first year after injury (see Figure 1). Two 
factors were found to be significantly related to the occurrence of PTH, prior history of headache 
and female gender. In this study, we found that 22-29% of the sample reported frequent 
headaches (multiple times per week/daily). This stands in contrast to what is reported for the 
non-brain injured general population in which 4-5% report chronic daily headache (greater than 
15 days per month).38-40  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1. Incidence and cumulative incidence of headache across 1 year after TBI. 
 
 
 
 
Recently, we reported the preliminary results of the second natural history study of PTH after 
mild TBI.41 We enrolled 220 persons admitted to the hospital for observation or for other injuries 
with mild TBI based on ACRM criteria. Baseline prevalence of headache prior to injury was 
17%. However, prevalence at 3 months was 73%, at 6 months 79%, and at 12 months 67%, even 
higher rates than for those with moderate-severe TBI. The majority of these headaches appeared 
to have characteristics of migraine or probable migraine headache. At 12 months, 25% had 
headaches that occurred several times a week. Impaired function (inability to engage in daily 
activities including work, school, household, or social activities) due to headaches was reported 
even by those with lesser frequency of headaches as seen in Figure 2 which is consistent with 
reports from those with moderate to severe TBI. More than 50% of reported headaches at 6 and 
12 months after injury were rated as having significant or severe impact on functioning in those 
with moderate to severe TBI. Figure 2. Headache Impact by Frequency 
0
10
20
30
40
50
60
70
80
90
100
Baseline
3 mo
6 mo
12 mo
% of Subjects with Headache
PTH Incidence
PTH Cumulative
Incidence

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There have been opposing points of view regarding the association of head injury 
severity and incidence of headaches where some believe that headaches occur primarily in mild 
injuries and others disagree.17, 18, 21 Our research indicates that headaches are common in all 
severities of TBI although the prevalence is higher in mild TBI.42  
PTH falls into the category of secondary headache. The International Headache Society 
(IHS) defines a secondary headache as one that occurs de novo with another disorder 
recognized to be capable of causing it, e.g., traumatic brain injury causing a PTH.43 The IHS 
acknowledges that the clinical characteristics of secondary headaches are poorly described in 
the scientific literature and therefore, does not use clinical characteristics of these headaches as 
part of their definition. In fact, the IHS classification of post-traumatic headache is defined by 
the latency of headache following injury, duration of the headache, and severity of the brain 
injury preceding the headache. According to this definition, an acute PTH must occur within 7 
days of injury. After 3 months, an acute PTH is considered to be a chronic PTH. The time 

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element that is included by the IHS in the definition of PTH, that is, that the headache must 
have an onset within the first week after injury, likely leads to an underestimation of PTH.19, 42 
Our work as well as that of Theeler et al44 has found that up to one-third of PTHs can first be 
recognized outside this window of time, therefore PTH may manifest in much the same way 
that post-traumatic epilepsy presents, occurring months to years after injury.45  
 In our research using classification criteria designed for the primary headache disorders, 
we found PTH to be characterized most frequently as migraine or probable migraine, followed 
by tension-type headaches, and cervicogenic headaches.25 It is also recognized that trauma to 
the head can result in worsening of a previous headache syndrome. We recently published an 
article that provides characterization of PTH in our cohort of individuals enrolled into the TBI 
Model System with moderate to severe TBI.25 Our study revealed that of those reporting 
headache, 63% met criteria for migraine and probable migraine using primary headache 
classification criteria for this cohort of prospectively studied individuals. Tension type headache 
accounted for 21% and cervicogenic headache for only 10%. Consistent with the general 
headache literature, females were more likely to have migraine headache and to have reported 
migraine headache prior to injury. Those with migraine headache also reported higher frequency 
of headaches compared to those with other headache types.  
 
Virtually all early reports of PTH have relied on populations with mild TBI and post-
concussion syndrome disorders. Many of the studies report on self-referred populations. Lew et 
al16 in 2006 reviewed all articles published in English on post-traumatic headaches in a 15 year 
period (145 in total) and found only 5 articles reporting studies that addressed the characteristics 
and types of headaches, and 10 articles on the treatment of PTH (2 single case reports, 3 case 

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series, 5 retrospective or uncontrolled prospective studies). Pooled data from these 5 studies 
indicated that for those with headaches, tension-type headaches were most common occurring 
in 33.6% of headache sufferers. Migraines occurred in 28.6% of the headache patients. More 
recent examination of characterization of PTH has come from studies conducted on military 
populations with similar results to our study.44, 46 In contrast to earlier research on PTH,18, 47, 48 
results from military populations suggest that characterization of PTH is consistent with higher 
rates of migraine type headache, over tension or cervicogenic.32, 49-52   
What is the current approach to treatment of PTH?: Currently, the literature on 
treatment of PTH suggests following guidelines for treating headache using general population 
studies on those with primary headache disorders.46, 53-55 However, all these recommendations 
also note the lack of randomized controlled trials in individuals with TBI and cite concerns in 
treatment trials of headache in a brain-injured population for the potential for more adverse 
effects from medication. In our survey of rehabilitation physicians and headache specialists, we 
found that physicians had difficulty utilizing headache type to drive treatment choice. Therefore, 
more data on defining characteristics of PTH and effective treatment of PTH is necessary. While 
physical therapy and counseling were among the most frequent choices of treatment among this 
group, the effectiveness of these treatments in this population is not known.26   
With no Class I randomized, prospective, blinded treatment trials of PTH, some 
clinicians have used migraine-specific therapy for PTH based on anecdotal evidence of success. 
Erickson et al conducted a retrospective review of PTH treatment in a clinic-based population of 
active duty soldiers, and found that the “triptans”, a class of migraine-specific medications, were 
effective in those suffering from moderate to severe PTH, both blast and non-blast related.56 

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Most, but not all, of these headaches had migraine characteristics. A breakdown of reported 
effectiveness did not specifically correlate headache characteristics with drug responsiveness. 
The rationale for treatment with migraine specific therapy is that though primary headache 
disorders may be due to an inherited disorder of transmission resulting in episodic brain 
dysfunction and PTH is thought to have a structural basis or potentially treatable cause relating 
to an injury, both may have a similar response to migraine-specific treatment based on a similar 
phenotype. Therefore, in moderate to severe PTH meeting classification criteria for migraine or 
probable migraine, the use of triptans has been thought to be a reasonable course of action. 
However, no research has been conducted on triptans in PTH to determine whether there may be 
different side effect profiles from primary migraine treatment or whether the medication can be 
taken appropriately (for example, that is has greater efficacy when taken at headache onset) by 
individuals with TBI.  
Why triptans? Pharmacological features of triptans and the concept of the 
physiological “common pathway”:  Migraine specific medications include the “triptans” which 
are serotonin 5-HT 1B/1D agonists that work to inhibit inflammatory peptide release (e.g., 
calcitonin gene-related peptide, CGRP, a potent vasodilator) in the meninges through the 
serotonin 1D receptor. Blocking release decreases a “pain signal” being generated from 
peripheral trigeminal nerves to the trigeminal nucleus caudalis which is thought to modulate or 
generate migraine. Triptans also bind to receptors on the meningeal artery endothelium via 
serotonin 1B (5-HT 1B) receptors causing vasoconstriction of vessels dilated by CGRP or other 
inflammatory peptides. 

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Based on evidence of multiple Class I studies, triptans are recommended for treatment of 
migraine at any level of pain. Sumatriptan was the first triptan approved by the FDA for 
treatment of migraine in 1993. It has been the most prescribed triptan and the gold standard 
against which all other triptans have been compared. It has proven efficacy and tolerability for 
the treatment of primary migraine. It comes in several oral doses (25 mg, 50 mg and 100 mg) and 
the 100 mg dose has been evaluated against placebo in 19 randomized, double-blind, placebo-
controlled clinical trials of migraine.  
There is evidence to show that if a single subject has a variety of headache types which 
include migraine (mixed headache disorder), then sumatriptan is effective for all headache 
phenotypes in that subject as compared to treatment of those individuals with headache disorders 
that do not include migraine (primarily mild-moderate, non-disabling headache). In this group of 
only non-migraine headache, sumatriptan is no more effective than placebo.57 This argues for a 
common underlying mechanism of different headache “types” in those who having a moderate to 
severe headache which fits the definition of “migraine” or probable migraine despite differing 
headache types at different times (mixed headaches), all of which are responsive to 5-HT 1B/1D 
agonists. Given anecdotal response to the triptans in PTH described in one observational study 
by Erickson56 and potential physiologic similarities between primary headache disorders and 
PTH, resulting in similar headache phenotypes, there may be a final common path with response 
to migraine medication in primary migraine and PTH which would provide clinicians with tools 
to effectively treat these headaches which have a significant impact on function following brain 
injury.  

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Indirect evidence for this common pathway comes from similarities between TBI and 
migraine in biochemical changes found in the brain. Increased extracellular potassium and 
intracellular sodium, calcium and chloride have been reported.58 Both migraine and PTH show 
excessive release of excitatory amines such as glutamate and aspartate. Intracellular and total 
brain magnesium has been found to decline in mild TBI and is thought to be low during and 
between migraine attacks. There is a change in the calcium/magnesium ratio in both conditions 
and nitric oxide, while potentially leading to tissue injury through free radical formation 
following TBI, is thought to be involved in migraine, as it is a potent vasodilator at the vascular 
endothelium.58 These similarities between neurochemical changes in TBI and migraine suggest a 
shared mechanism of headache occurrence by way of a “final common path.”59 Since the 
migraine pathway is thought to involve activation of the trigeminovascular system and the 
release of inflammatory neuropeptides, causing neurogenic inflammation which is blocked by 
sumatriptan, it is plausible that direct physical force from TBI can cause the biochemical changes 
discussed above also activating the trigeminovascular system and causing neurogenic 
inflammation and therefore, responding to treatment with a drug so far only approved to treat the 
moderate to severe headaches known as migraine.  
V. 
 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 

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individuals with mild (with adequate documentation or in the opinion of study 
physician), moderate and severe 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.  
VI. 
 Overview of Study Design 
This phase II evaluation of sumatriptan as a treatment for PTH will examine the methods and 
approach necessary to take the next step to a phase III trial. The sample will include 40 
individuals with mild (with adequate documentation or in the opinion of study physician), 
moderate and severe TBI who will be recruited primarily from patients within UWTBIMS and 
from outpatient clinics and brain injury related organizations to be followed over 3 months. We 
plan to enroll individuals with moderate to severe headache who experience at least two and up 
to a maximum of fifteen moderate to severe headaches per month. Severity will be rated using 
a 4 point pain scale (0=no headache, 1=mild headache, 2=moderate headache, 3=severe 
headache). Headache classification will be confirmed by clinician interview. 
 

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Table 1. Summary of Protocol for Proposed Study of Sumatriptan for PTH   
 
Pre-Screening 
Visit 1  
(Day 1) 
Days 1-29 
Visit 2  
(Day 30) 
Days 31-89 
Visit 3  
(Day 90) 
Inclusion/ 
Exclusion 
Criteria 
Consent  
 
Headache 
questionnaire 
 
 
All subjects 
trained in use of 
headache diary  
 
Daily headache 
diary 
 
Weekly 
telephone calls 
 
Daily headache 
diary reminders 
(phone, text, 
email) 
Evaluate 
headache diary 
for eligibility 
(pre-visit) 
 
Baseline 
assessment (if 
meets headache 
diary eligibility) 
 
History, clinical 
headache 
interview and 
physical 
examination 
 
Dispense drug if 
eligible 
Daily 
headache 
diary 
 
Study drug 
use per 
instruction 
 
Weekly 
telephone 
calls 
 
 
Follow up 
Assessment 
 
Drug count 
 
 
 
 

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 Population 
A. Inclusion criteria: 
A subject will be eligible for enrollment into this study if all of the following criteria are met: 
• Age 16-65. 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 mild (with adequate documentation or in the opinion of study physician), 
moderate or severe TBI occurring at least 2 weeks but not greater than 60 months before 
enrollment. Two weeks was chosen to include only those subjects who are having 
headache beyond their acute injury and 60 months was chosen  to ensure that the 
headache may reasonably be connected to the TBI.   
• Subject has at least two and up to a maximum of fifteen total moderate to severe 
headache days per month. Subject report of meeting this criterion 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 obtains a score of 25 or greater on the Mini Mental Status Examination63 or has a 
caregiver to monitor implementation of study procedures including the headache diary 
and medication regimen.  

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• 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. 
B. Exclusion criteria: 
A subject will not be eligible to participate in this study if any of the following criteria apply: 
• 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. 

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• 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. 
C.  Sample Size 
• This is a single arm, unblinded study and is being undertaken to test necessary study 
instruments and procedures, establish feasibility and determine side effects in a 
population with moderate to severe TBI in preparation for a subsequent Phase III study. 
Therefore, we are using forty subjects as a reasonable sample size to meet these aims.   
 
 

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VII. 
Overview of Study Procedures 
A. Recruitment 
Description of the recruitment process: Subjects enrolling in the UWTBIMS will be 
provided information regarding the study and asked for permission to call them post 
discharge from the hospital (and at least two weeks out from their injury) for screening. 
Additionally, subjects enrolled in the UWTBIMS over the 60 months prior to the study start 
date will be called for screening if they had indicated on their prior consent form interest in 
being contacted for future studies. If there is interest in study participation, then a pre-
screening survey for inclusion/exclusion criteria will be given. Also, subjects will be 
recruited from outside the TBI MS, including outpatient headache and TBI clinics, and be 
advertised through related organizations such as the Washington Brain Injury Alliance.  
There will also be advertising on our own TBI MS website. Study information emails using 
study brochure will be sent out to UW providers on a monthly basis to aid with recruitment.  
A provider may respond with the name and medical record number of a potential subject 
whom the provider has spoken to about the study and given verbal permission for the 
coordinator to contact for screening. 
 
Subjects will be encouraged to bring a family member or caregiver with them to any 
screening or research appointments. Participants who are under 18 will be required to bring a 
parent or guardian with them to their research appointments. As part of the process to 
evaluate participants’ ability to comply with the use of the headache diaries and study drug, 
these family members/caregivers will be interviewed about the amount of assistance needed 

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by the subject and any discrepancies in subjects’ reports. In our prior study, while family 
member/caregivers were not able to give details of headache characteristics, we did find that 
they were able to report accurately the occurrence of headaches when compared to subjects’ 
reports. 
B.  Data Collection and Measures   
Data collection will occur at enrollment, and at each clinic visit.  Table 2 provides a summary 
of the measures that are collected at each step in the study. Figure 3 outlines all activity over 
throughout the duration of the study.  A full description of each measure and the reason for 
its use follows the table. (Table 2:  List of measures.) 
Table 2. List of measures 
Assessment 
Timeline 
 
Pre-Treatment 
Visit 
(Clinic Visit 1) 
Treatment Visit 
(Clinic Visit 2) 
Outcome 
Assessment 
(Clinic Visit 3) 
INITIAL SCREENING MEASURES 
 
 
 
 
Mini Mental State Examination63 
X 
 
 
Demographic Questionnaire 
X 
 
 
Headache History Questionnaire 
X 
 
X (since study 
start) 
Headache Diary 
X ( to be kept 
for 1 month) 
 
 
Medical History and Physical Examination  
X 
 
 
Weekly Compliance Phone Calls 
X 
X 
 
Pregnancy Test (if needed) 
 
X 
 
COGNITIVE MEASURES 
  
 
 
 
 Cognitive Assessment 
*1. Rey Auditory Verbal Learning Test (RAVLT)64 
*2.Trail Making Test (TMT)65 
*3.Wechsler Adult Intelligence Scale – IV (WAIS-
IV), Processing Speed Index66 
 
X 
 
X 
X 
 
SELF REPORT AND EMOTIONAL HEALTH 
MEASURES 
 
 
 
 

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*Physician Health Questionnaire-9 (PHQ-9)67 
 
X 
X 
General Anxiety Disorders 7 (GAD-7)68 
 
X 
X 
Analog Pain Scale69  
 
X 
X 
Insomnia Severity Index70 
 
X 
X 
Brief Pain Overview71 
 
X 
X 
*EuroQol72 
 
X 
X 
*Satisfaction with Life Scale (SWLS)73 
 
X 
X 
*Rivermead Post Concussion Symptom 
Questionnaire (RPQ)74 
 
X 
X 
OUTCOME MEASURES  
 
 
 
 
Headache Diary  
 
X (kept 
throughout 
treatment period) 
X 
Headache Impact Test 6 (HIT-6)75 
 
X 
X 
Compliance measures (Headache diary completion 
percentage, medication counts 
 
X 
X 
Reduction in number of headaches and pain relief 
 
X 
X 
Number and type of adverse events 
 
X 
X 
*indicates measures which are part of the Common Data Elements for TBI 
Measures were chosen to best assess domains of interest for this project. Where 
applicable, measures were chosen that are part of the Common Data Elements for TBI 
recommended as a result of a scientific initiative led by several sponsoring federal agencies 
(NINDS, NIDRR, VA, DCOE, and DVBIC) and the results of which were published in a special 
edition of Archives of Physical Medicine and Rehabilitation (2010, Volume 91 (11)) and which 
have been recently updated for Rehabilitation of Moderate to Severe TBI (TBI Version 2.0 CDE 
Review Package, http://www.commondataelements.ninds.nih.gov/TBI.aspx#tab=Data_Standards).  
The purpose of using Common Data Elements is to allow comparisons between studies, ease 
scientific communication, and accelerate accumulation of scientific knowledge. Three of the 
content experts involved in the CDE initiatives are investigators on the proposed study (Dikmen, 
Temkin and Bell). The headache questionnaire has been used in our prior natural history studies 

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and is available for review in Appendix A along with the proposed flow chart for the headache 
diary. 
C. Primary Outcome Measure:  Resolution of headache 2 hours after drug is taken. 
D. Secondary Outcome Measures:  
a. *Physician Health Questionnaire-9 (PHQ-9)67,  
b. General Anxiety Disorders 7 (GAD-7)68,  
c. * Analog Pain Scale69,  
d. Insomnia Severity Index70,  
e. *Brief Pain Overview (BPO)71,  
f. *EuroQol72, *Satisfaction with Life Scale (SWLS)73,  
g. *Rivermead Post Concussion Symptom Questionnaire (RPQ)74,  
h. Headache Impact Test 6 (HIT-6)75, 
i. compliance measures (headache diary completion percentage,  
j. medication counts, reduction in number of headaches and pain relief, number and 
type of adverse events.  
k. Injury type and severity, medication use, and accompanying disorders.  
l. Data on cognitive status to ascertain appropriateness for participation and to 
further characterize the population with respect to ability to use headache diary.  
i. Mini Mental State Examination63,  
ii. Rey Auditory Verbal Learning Test (RAVLT)64,  
iii. Trail Making Test (TMT)65,  
iv. Wechsler Adult Intelligence Scale – IV (WAIS-IV) 

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v. Processing Speed Index66. 
E.  Rationale/Explanation for Measure Selection: 
Headache relief, frequency and severity are the most frequently used measures of medication 
efficacy in headache research. The headache survey and HIT-6 will further characterize the 
headache syndrome and functional impacts of headache. The headache survey will gather 
information on several factors that will be used to comprehensively describe PTH and its 
treatment including International Classification of Headache Disorders, 2nd edition (ICHD) 
criteria (type of headache by characteristics such as location, duration, severity, associated 
symptoms).76 This measure was developed by our group and used for the multi-site study on 
the natural history of headache after TBI funded by NIDRR through the TBI Model 
Systems5 program and a second single site field-initiated study funded by NIDRR to 
examine the natural history of headache in individuals with mild TBI.  
The Mini Mental State Examination63 will be administered at the screening visit.  Any 
score greater than or equal to 25 points (out of 30) indicates a sufficient cognitive level likely 
to enable a subject to participate without support. A lower score would indicate that the 
support of a caregiver would likely be necessary for successful adherence to the study 
protocol.  
The other cognitive measures (Rey Auditory Verbal Learning , Trail Making Test, 
WAIS IV Digit Symbol, and WAIS IV Symbol Search) will be given at the clinic visit on 
Clinic Visit 2 to characterize the population.  
The RPQ is a well-validated measure of post-TBI symptoms/severity and is used to 
measure other symptoms that may impact headache. Other measures were selected to capture 

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the areas of functioning expected to be impacted by headache and to change as a function of 
treatment. The EuroQoL and Satisfaction with Life Scale (SWLS) are intended to examine 
not only functional independence in various activities of everyday life, but also satisfaction 
with that quality of life. The PHQ-9, GAD-7, BPO, Analog Pain Scale and ISI measures will 
allow for evaluation of frequently co-occurring disorders (pain, sleep disorders, and 
depression) and broader response to the intervention.   
 
A negative pregnancy test will be required for any female of child-bearing years. 
F.  Headache Diary:  As there are no biomarkers for headache or headache severity, 
headache diaries are used to concurrently record the characteristics, frequency, and 
severity of headaches and the response to treatment and have been successfully used in a 
variety of populations, including children.77 We will ask the subject to fill out a headache 
diary each day during the study to rate the frequency and severity of headache, simple 
headache characterization, and response to study drug.  This diary will be available on a 
smart phone application, via a secure internet survey or on paper, depending on the fit for 
the participant. The paper-based diary is rated at a 3rd grade reading level.  The research 
assistant will practice filling out the diary with the subject prior to discharge from the 
hospital and will review on the weekly telephone calls. [See Attachment 19 for headache 
diary content] 
 
 

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VIII. 
 Enrollment and Visits (See Table 2, Figure 3) 
Enrollment:  Subjects enrolling in the UWTBIMS will be provided information regarding the 
study and will be asked for permission to call them post discharge from the hospital for 
screening. Additionally, subjects enrolled in the UWTBIMS over the 60 months prior to the 
study start date will be called for screening if they had indicated on their prior consent form 
interest in being contacted for future studies. If there is interest in study participation, then a 
pre-screening survey for inclusion/exclusion criteria will be given. Additionally, subjects will 
be recruited from outside the TBI MS, including outpatient headache and TBI clinics, and be 
advertised through related organizations such as the Brain Injury Alliance.   
 
Subjects will be encouraged to bring a family member or caregiver with them to any screening or 
research appointments. Again, participants under 18 will be required to bring a parent or 
guardian with them to their study visits. As part of the process to evaluate participants’ ability to 
comply with the use of the headache diaries and study drug, these family members/caregivers 
will be interviewed about the amount of assistance needed by the subject and any discrepancies 
in subjects’ reports. In our prior study, while family member/caregivers were not able to give 
details of headache characteristics, we did find that they were able to report accurately the 
occurrence of headaches when compared to subjects’ reports. 
 
Description of obtaining informed consent: Subject Informed Consent will be obtained after 
pre-screening and prior to any collection of any study data. Subjects will be emailed or given a 
copy of an ICF (Informed Consent Form) prior to their baseline clinic visit. This will allow extra 

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time to review study procedures, however it is not required for them to review the consent form 
before meeting with research staff.  All interested participants will be consented in a private 
conference room or exam room by the study coordinator or research assistant. Each page of the 
ICF will be reviewed with the subjects. For those subjects scoring <25 on the MMSE, an 
authorized proxy will be consented and we will document the assent of the subject. Subjects will 
be given ample time to ask if anything is unclear about the study and what is expected of them as 
participants in the study. The subjects will be encouraged to ask questions about the study. Once 
all questions are answered, subjects and proxies will be asked to voluntarily sign and date the 
ICF. The person conducting the Informed Consent discussion will sign and date the consent 
form. The original ICF will be filed in a  study binder stored separately from subject’s study ID. 
 
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 
questions.  This will document the number of headaches, headache severity, headache days and 
description of their headache and associated symptoms.  This will assist in determining 
compliance and ability to complete this portion of the study, and ensure that the frequency of 
headaches is sufficient to include into study intervention (See Attachment 9 Study Sequence 
Flow Sheet). Research staff will meet with the subject (and caregiver) to provide training on 
headache diary utilization and will contact them on a daily and/or weekly basis to answer 
questions and maximize accuracy and compliance with the diary, depending on the subject’s 
preference. Proper utilization of a headache diary and success of data input by the subject and 
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headache diary will be available in multiple forms. We will have iPod Touch devices loaded with 
a headache diary application that will allow for direct entry of responses onto a security 
protected survey site and will include reminders for daily completion as well as prompts for 
efficacy of drug treatment used. However for those who prefer, a computer accessed web-based 
headache diary (otherwise similar to the iPod version) and a paper version with identical 
questions will be available. For those who choose the alternate forms of diary, a clip-on timer 
will be provided for recording of headache duration and reminders may be sent as text messages 
or emails based on subject preference.  
 

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Treatment Visit (Visit 2): 
Medical History and Physical Examination. A medical history will be obtained at the first visit 
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 at the second visit 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. The headache diary will be reviewed before the 
treatment visit is scheduled, and patients who disqualify based on the classification of their 
headaches will not be scheduled to come in for Visit 2, as this would be an undue and 
unnecessary burden given they will not be continuing with the study. . 
 
Data Collection at Treatment Visit (Visit 2): Headache histories will be assessed after 30 days 
(+/- 3 days), 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.  (See Table 2). 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 and will not participate in Visit 2.  This is due to the lack of evidence that 
sumatriptan is effective for the treatment of non-migraine types of headache.   
 

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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 to a 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.  Measures 
administered on this visit will include: 
1) Interim medical history form (new diagnoses, changes in medications) 
2) Headache Survey 
3) Headache Impact Test (HIT-6) – Questions about headaches and how much 
they affect patient’s life. 
4) Satisfaction with Life Scale (SWLS) – Questions about how satisfied patient is 
will life. 
5) Rivermead Post-Concussion Symptoms Questionnaire (RPQ) – Questions 
about the 16 most common  symptoms after concussion. 
6) Patient Health Questionnaire (PHQ-9) – Questions about symptoms of 
depression. 
7) Brief Pain Overview (BPO), Analog Pain Scale - Questions asking about pain. 
8) Insomnia Sleep Index (ISI) – Questions about sleeping habits. 
9) Euroqol – Questions about quality of life. 
10) Brief Symptom Inventory – Questions about other symptoms. 
 
 

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Figure 3:  Subject Participation Summary 
 
Visit 1 
45-60 minutes
Day 1
Visit 2
30-90 minutes
Day 30
Visit 3
 45-60 minutes
Day 90
Weekly Telephone Check-in 
(Day 30-Day 90)
Answer Headache Questions Daily
(web application or email)
(Day 30 – Day 90)
 
Pre-Treatment Telephone Weekly Check in 
(Day 1 – Day 30)
 
Sumatriptan for Treatment of Headaches
 (Day 30-90)
Pre-Treatment
Treatment
Answer Headache Questions Daily
(web application or email)
(Day 1 – Day 30)
 
 
Subject Instruction: During the Visit 1, research staff will explain headache diary and 
demonstrate usage to ensure patient (and caregiver if present) understand.   Instructions will 
include how and when to take the study medication.  Their pain will be assessed 2 hours 
following use of sumatriptan, this will include: 
1. pain presence 
2. severity throughout the first 24 hours after use of the study drug 
3. whether there was a need for 2nd dosage of sumatriptan 
4. Whether there was any use of any rescue medications 
5. Whether there was recurrence of pain.  

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Written and verbal instructions will be given on which drugs to avoid during the 
study, acceptable drugs to use for rescue therapy, and what to do in the case of an 
adverse event.  
IX. 
Treatment with Sumatriptan Procedures 
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. After 60 days, all subjects will be given 
an outcome assessment.  The measures included in this assessment are shown in Table 2. 
Compliance: Compliance will be assessed during the weekly telephone follow-up calls to 
subjects and caregivers and we will have subjects return their medication packs and any unused 
medication at Visit 3. Any lack of compliance to the study protocol will be recorded on case 

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report forms for that subject. Subjects will be encouraged to improve compliance and the 
research staff will assist the subject and/or caregiver in problem solving compliance issues, 
including suggesting to subjects that staff contact them either via email, telephone or text with 
daily reminders to complete their headache entry.  
 
Medication administration:  The study drug will be distributed in blister packs. Subjects will be 
instructed to decrease the dose by 50% (cut the tablet in half) if side effects occur after the first 
dose. They will also be required to contact the research staff to report the side effects. If the side 
effects continue to be intolerable, that subject will be discontinued from the intervention portion 
of the study but will be asked to continue keeping their headache diary.     
 
Rationale for Dosage Selection and Medication Administration Procedures: The 
recommended initial dosage of Sumatriptan is 100 mg76 and this is the most commonly 
prescribed dose in primary care as well as neurology or headache specialty clinics. In a meta-
analysis of 53 clinical trials involving sumatriptan,77 100 mg of Sumatriptan resulted in 29% of 
patients becoming pain free at 2 hours (moderate to severe pain to no pain) vs. placebo. This is a 
much more rigorous end-point than the pain relief response which showed a 59% headache relief 
response (moderate to severe to mild or no pain) vs. placebo. Rescue medications will include 
acetaminophen, ibuprofen, or other analgesic as prescribed by the subject’s own physician; 
detailed instructions will be provided to the subjects.  
A. Subject Discontinuation:  Subjects may be discontinued from the study drug by their 
request or if the subject experiences an adverse effect sufficient to warrant withdrawal 

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from the study drug. In the case of discontinuation of study drug, the reason will be 
recorded and the subject will be asked to continue to monitor their headaches with use of 
the headache diary and to participate in a final assessment.   
 
Compensation:  Subjects will be given $25 upon completion of each of the three clinic 
visits (total $75). This compensation is to defray the cost of phone use, 
transportation/parking cost, and any meals and to compensate subjects for their time.  
Subjects will also have their parking costs validated. 
 
X. 
 Data Analysis 
Study Sample Size and Rationale: This is a single arm, unblinded study and is being 
undertaken to test necessary study instruments and procedures, establish feasibility and 
determine side effects in a population with mild (with adequate documentation or in the 
opinion of study staff) moderate, or severe TBI in preparation for a subsequent Phase III 
study. Therefore, we are using forty subjects as a reasonable sample size to meet these aims.   
 
Case Availability:  We anticipate no difficulty in recruiting 40 subjects to participate. Given 
our natural history study,19 we expect at least 48% of TBIMS subjects to have headaches that 
qualify in terms of both frequency (4 to 15 headaches per month) and severity (rating of 2 or 
3 on the 4 point scale), (26% had qualifying headaches at 3 months, another 10% who did not 
qualify at 3 months had qualifying headaches at 6 months and another 12% who had not 
qualified previously had qualifying headaches at 12 months). The UWTBIMS expects to 

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recruit at least 45 patients per year. Those entered in the first 3.5 years of the upcoming cycle 
(45*3.5=158 TBIMS participants) will be eligible for the headache study. Additionally, 
because eligible subjects can be between 3 and 60 months post-injury at recruitment, we will 
be able to contact the UWTBIMS subjects enrolled in the previous 60 months who indicated 
interest in being contacted for future studies.  
 
Data Analysis: Data analysis for the feasibility and safety aims will be primarily descriptive. 
We 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. We will present a 
confidence interval for each estimate. To get preliminary data on efficacy of sumatriptan, we 
will compare headache control before and after the participants start taking sumatriptan. We 
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. We 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. We will descriptively examine any differences 
in compliance, side effects, and feasibility based on cognitive functioning, as well as by other 
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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.  
 
XI. 
Data Management 
Assessment data and some headache diary data will be collected on paper forms and entered 
locally into a specially-designed Access database that incorporates data quality checks. 
Device and web-based headache diaries will be entered directly into a Catalyst survey site 
(located on a secure, password protected server). All files will be password protected to 
ensure only authorized personnel can view or change them. Data will be uploaded to the 
Biostatistics Unit monthly. Data are stored on a University of Washington secure server that 
is backed up nightly. More sophisticated checks than can be implemented at the time of entry 
will be run monthly, generating queries for the staff to evaluate and correct if necessary. 
Neuropsychological tests will be double checked and double scored. Reports monitoring the 
progress of the study will be generated monthly to help the investigators identify areas such 
as enrollment or follow-up rates that might need specific attention. Analyses will be 
performed using SPSS or SAS. 
A. Identifiers and confidentiality: Data will be identified by study number and coded initials 
(MS replacing true initials NT), not universal identifiers such as name or hospital 
number. Study number, rather than name will be on data collection forms (other than the 
form that gathers contact information). Study files will be kept in a locked cabinet or 
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Identified information such as phone numbers needed to contact the participant and 
consent forms will be kept in separate files from the study data. 
B. Study staff will have access to study records as will representatives of the human 
protection offices and representatives of the funding agency. The study will not 
intentionally collect any data that would need to be shared with state or local authorities. 
If the subject responds to questionnaire items or volunteers information about intent to 
harm themselves or others, we have a standard IRB approved protocol that will be 
enacted to manage such disclosures to ensure subject or others safety.  
C. If the subject reveals suicidal ideation on the PHQ-9, one of the clinician investigators 
will be notified immediately to evaluate the subject. If the investigator is convinced that 
active suicidal ideation or plan is NOT present, we will resume evaluation and 
participation in the study. If the provider is concerned that the subject has active suicidal 
ideation and/or plan, we will use suicide management protocols that have are approved 
by our Institutional Review Board and include specific algorithms to assess risk, use of 
local Crisis Clinic numbers and 24/7 back-up by MD or PhD staff who can conduct more 
comprehensive assessments, and make referrals as needed, including escorting the subject 
to the emergency department. 
D. Disposition of data: Hard copy data will be stored in locked file cabinets or locked rooms 
while the study is ongoing. When the study is complete, the data will be sent to a secure 
archive like that used for medical records. Washington state law requires clinical trial 
data be retained for 25 years. At the end of that time, the data will be destroyed. 
Electronic data will be encrypted and stored on secure University of Washington servers. 

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At the end of the study, each investigator will get a copy of the de-identified data. At the 
end of the study, all local copies of the encrypted contact information files will be 
destroyed. 
E. Sharing study results: As this will be an open-label study, each subject will be able to 
personally decide whether sumatriptan was helpful to them. We will offer to send a letter 
summarizing the study to the subjects’ primary health care provider to allow for further 
prescriptions if the subject desires. While the study drug may be of benefit to an 
individual subject, the main sharing of study results will be with the general public and 
medical community which may benefit from our study outcome. Further information on 
information sharing is contained in Section D, Plan of Dissemination Activities. 
F. Laboratory evaluations: This study will not collect any specimens nor do any laboratory 
evaluations other than a pregnancy test in female subjects at randomization, and those 
results will be immediately communicated to the subjects. 
XII. 
 Plan of Evaluation 
The research team, under the direction of Dr. Hoffman, has outlined a plan that provides for 
periodic evaluation of the progress towards study outcomes, quality of data collection and entry, 
and dissemination with clear assignment of responsibilities for these tasks.  Performance 
measures were chosen for their relevance in achieving the specific aims of the study and in 
assessing the impact on the stakeholders for this study (including researchers, health care 
providers, and most importantly, consumers).   
 

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Review of performance will be conducted through: (1) review of staff performance by Dr. 
Hoffman, (2) review of human participants’ protection measures by the IRB, (3) review of 
overall performance and responsiveness to consumer concerns by the UW TBI Model System 
consumer advisory panel, and (4) review of scientific rigor of publications and presentations 
outside reviewers.  The PI, co-investigators, and study staff will meet weekly to assess study 
progress and quality assurance. Research staff will receive ongoing supervision and feedback in 
these meetings from Dr. Hoffman and Ms. Glorieux.  Data completeness, timeliness, and quality 
will be tracked by Ms. Glorieux in conjunction with Dr. Hoffman.   
 
 

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XIII. 
 Objective and Quantifiable Performance Measures 
Project outcomes for which performance measures have been developed are: (1) Pre-Enrollment 
Activities, (2) Post-Enrollment Activities, and (3) Data Analysis / Dissemination (See Table 4 
for complete listing of performance measures).  There will be substantial pre-enrollment 
activities that will be addressed including completion of the manual of procedures, obtaining full 
IRB approval, database construction and testing, research staff training, equipment certification, 
pharmacy set-up, and subject binder/headache diary application completion.  Post-enrollment 
activities include subject recruitment and retention, completion of all data collection, monitoring 
of data safety and data audit and clean-up.  Data analysis and dissemination will consist of 
primary and secondary reports (presentation and publications) from the study, and design and 
submission of a Phase 3 trial (if the results so indicate). 
 
XIV. 
Safety and Adverse Events 
Pill counts will be conducted at each visit and a current medication list will be obtained for study 
physician review.  Daytime queries by the subject will be triaged by the research assistant. For 
nighttime or weekend queries, the subject will have access to a 24 hour paging operator to 
contact a physician in case of question relating to the study medication.  Dr. Natalia Murinova, a 
neurologist with expertise in headache treatment, has agreed to be the Safety Monitor.  She will 
receive a quarterly report of all Adverse Events and will be contacted by the study team within 
24 hours of any Serious Adverse Event to review with the study physician.  Any serious adverse 
event will be reported to the Human Subjects Division as well immediately. 
A.  Definitions 

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a.  Unanticipated Problems Involving Risk to Subjects or Others:  Any 
incident, experience, or outcome that meets all of the following criteria: 
b. Unexpected in nature, severity, or frequency (i.e. not described in study-
related documents such as the IRB-approved protocol or consent form, the 
investigators brochure, etc) 
c. Related or possibly related to participation in the research (i.e. possibly 
related means there is a reasonable possibility that the incident experience, or 
outcome may have been caused by the procedures involved in the research) 
d. Suggests that the research places subjects or others at greater risk of 
harm (including physical, psychological, economic, or social harm). 
e. An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens in severity during the course of the study.  Intercurrent 
illnesses or injuries should be regarded as adverse events.   Abnormal results 
of diagnostic procedures are considered to be adverse events if the 
abnormality: 
•  results in study withdrawal 
•  is associated with a serious adverse event 
•  is associated with clinical signs or symptoms 
•  leads to additional treatment or to further diagnostic tests 
•  is considered by the investigator to be of clinical significance 
Adverse events are classified as serious or non-serious.   
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•  fatal 
•  life-threatening 
•  requires or prolongs hospital stay 
•  results in persistent or significant disability or incapacity 
•  a congenital anomaly or birth defect 
•  an important medical event 
Important medical events are those that may not be immediately life 
threatening, but are clearly of major clinical significance.   They may 
jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment 
of bronchospasm in an emergency department would typically be considered 
serious.  All adverse events that do not meet any of the criteria for serious 
should be regarded as non- serious adverse events. 
g.  Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of the 
study treatment follow-up. For this study, the study treatment follow-up is defined 
as 30 days following the last study clinic visit. 
h.  Preexisting Condition 

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A preexisting condition is one that is present at the start of the study.  A 
preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens during the study period. 
i.  Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained. At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this 
study.  The investigator should notify the Data Safety Monitor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated 
study participation that may reasonably be related to this study.     
j.  Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if 
any one of the following conditions is met: 
•  The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality. 
•  The abnormality suggests a disease and/or organ toxicity. 
•  The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
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Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol. Any condition responsible for surgery 
should be documented as an adverse event if the condition meets the criteria for 
and adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
1. 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  
2. 
Surgery should not be reported as an outcome of an adverse event if the purpose 
of the surgery was elective or diagnostic and the outcome was uneventful. 
B.  Recording of Adverse Events 
At each contact with the subject, the study staff must seek information on adverse events by 
specific questioning and, as appropriate, by examination.   Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should recorded in the source document, though 
should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course 
of each event should be followed until resolution, stabilization, or until it has been 

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determined that the study treatment or participation is not the cause.   Serious adverse events 
that are still ongoing at the end of the study period must be followed up to determine the final 
outcome. Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be recorded and reported 
immediately. 
Minimum information required for each AE includes type of event, duration (start and end 
dates), severity, seriousness, causality to study, action taken, and outcome. 
 
C.  Evaluating Adverse Events 
Assessment should include the intensity (severity) of the event and the relationship to Study 
Agent(s)/Intervention(s). 
Severity of AEs will be graded by the Investigator using the following criteria as guidelines: 
1. 
Mild: Nuisance, barely noticeable. 
2. 
Moderate: Uncomfortable, troublesome symptoms not significantly interfering with 
daily activities or sleep. 
3. 
Severe: Symptoms significantly interfere with daily activities or sleep. 
The relationship of the AE to the study drug should be specified by the Investigator, using 
the following definitions: 
• Not Related: Concomitant illness, accident or event with no reasonable association with 
treatment. 
• Unlikely: The reaction has little or no temporal sequence from administration of the study 
drug, and/or a more likely alternative etiology exists. 

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• Possibly Related: The reaction follows a reasonably temporal sequence from 
administration of the drug and follows a known response pattern to the suspected drug; 
the reaction could have been produced by the study drug or could have been produced by 
the subject’s clinical state or by other modes of therapy administered to the subject. 
• Probably Related: The reaction follows a reasonable temporal sequence from 
administration of study drug; is confirmed by discontinuation of the study drug or by re-
challenge; and cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. 
• Definitely Related: The reaction follows a reasonable temporal sequence from 
administration of study medication; that follows a known or expected response pattern to 
the study medication; and that is confirmed by improvement on stopping or reducing the 
dosage of the study medication, and reappearance of the reaction on repeated exposure. 
D.  Reporting of Serious Adverse Events and Unanticipated Problems 
1.  Investigator Obligations 
Investigators must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum 
those events that must be promptly reported are those that are: 
•  serious and related to study participation; 
•  serious and unexpected; and 
•  any other unanticipated problem involving risks to subjects or others 
 

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The study period during which adverse events must be reported is normally defined as the 
period from the initiation of any study procedures to the end of the study treatment 
follow-up. For this study, the study treatment follow-up is defined as 30 days following 
the last administration of study treatment. 
2.  Notifying the Principal Investigator 
Any study-related unanticipated problem posing risk of harm to subjects or others that are 
not Adverse Events should be reported on the “Unanticipated Problems Form”.  Any 
type of serious adverse event, must be reported to the Principal Investigator or designee 
within 1 business day of the event.  To report such events, a “Serious Adverse Event 
Form” must be completed and delivered to the Principal Investigator or designee within 1 
business day.   
3.  Notifying the Local IRB 
Within the following 48 hours, the investigators must provide further information on the 
serious adverse event or the unanticipated problem in the form of a written narrative.   
This should include a copy of the completed Serious Adverse Event form, and any other 
diagnostic information that will assist the understanding of the event.   Dr. Hoffman or 
her designee is responsible for safety reporting to the UW IRB and complying with their 
reporting requirements.   Copies of each report and documentation of IRB notification 
and receipt will be kept in the study file.   
4.  Notifying the Data Safety Monitor 

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Unanticipated  problems  posing  risks  to  subjects  or  others  and  serious  adverse  
events associated with the research will be forwarded to the Data Safety Monitor of the 
study within 24 hours. 
5.  Stopping Rules 
There are no planned interim or futility analyses. The Data Safety Monitor may 
recommend stopping for safety. 
6. Independent Data Safety Monitor 
The Data Safety Monitor is required to review all unanticipated problems involving risk 
to volunteers or others, serious adverse events and all volunteer deaths associated with 
the protocol and provide an unbiased written report. At a minimum the Data Safety 
Monitor should comment on the outcomes of the event or problem and in the case of a 
serious adverse event or death comment on the relationship to participation in the study.  
The Data Safety Monitor should also indicate whether he/she concurs with the details of 
the report provided by the study investigator. 
XV. 
 Ethical Considerations/Protection of Human Subjects 
Ethical Conduct of the Study 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 Institutional Review Board (IRB) 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 

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study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator.  
 Subject Information and Informed Consent 
This study will be conducted in compliance with Title 45 Part 46 of the CFR pertaining to 
informed consent.  At the first visit, prior to initiation of any study-related procedures, subjects 
will give their written consent to participate in the study.  Subjects will be provided information 
about the purpose of the study, participation/termination conditions, risks, and potential benefits.  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the participants and their families. 
Consent forms describing in detail the Study Agent(s)/Intervention(s) study procedures and risks 
are given to the participant and written documentation of informed consent is required prior to 
starting study agent/intervention. Consent forms will be IRB approved and the participant will be 
asked to read and review the document. Upon reviewing the document, the investigator will 
explain the research study to the participant and answer any questions that may arise.  The 
participants will sign the informed consent document prior to any procedures being done 
specifically for the study.   The participants should have sufficient opportunity to discuss the 
study and process the information in the consent process prior to agreeing to participate.  The 
participants may withdraw consent at any time throughout the course of the study.  A copy of the 
informed consent document will be given to the participants for their records. The rights and 
welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 

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 Sample Characteristics that Raise Special Concerns 
We do not anticipate that sufficient cognitive impairment will exist in any of the participants to 
the level that would impair the ability to give consent for participation.  However, those with 
more significant cognitive impairment will be identified at screening and will have a caregiver to 
monitor them on a daily basis. 
 
 

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XVI. 
 Risk/Benefit Assessment 
Possible risk: 
• Some people may experience side effects to sumatriptan including sensations such as 
chest tightness, tingling, muscle tightness. These are usually mild and transient, and 
rarely require urgent care.   
• Although rare, some people may experience allergic or hypersensitivity reactions to 
sumatriptan and may need to contact a physician.  
• Excessive use of sumatriptan can cause overuse headaches.   
• Sumatriptan is contraindicated in pregnant women and people with ischemic cardiac, 
cerebrovascular or peripheral vascular disease because of its vasoconstrictive effects 
mediated by weak 5HT-2 binding. Some subjects may have subclinical disease. 
• Subjects may be asked personal questions regarding such topics as depression and 
insomnia, and may be asked whether they have thoughts of death or suicide. This may 
cause some emotional discomfort. 
• There is a risk that this private information about them may be disclosed. 
• Unexpected detection of a potential diagnosis such as major depression may carry with it 
the risk of emotional distress. 
 Risk management and emergency response: 
A study or on-call physician will be available 24/7 in case of side effects or adverse events 
related to the study drug. The consent form will indicate the name and contact numbers of the 
study physicians.   There will also be a business card sized contact card with phone numbers 
given to subjects when study medication is given.  Depending on the event, the physician may 

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direct the subject to call 911 or go to an emergency department. If the reaction is a typical side 
effect of the medication, the physician may instruct the patient to continue or to stop taking the 
study drug. If the reaction is sufficiently severe, the research coordinator will be notified and the 
patient will be discontinued from taking further study medication.  
 
Subjects will be given 2 packages of 9 tablets of study drug at Day 30, each package to be 
opened at the start of that month. This amount is not expected to cause medication overuse 
(rebound) headaches. Subjects will be instructed not to take non-study sumatriptan, or any other 
triptan, for headache or any other reason while on study medication. A list of alternative 
medications will be provided to take if needed for rescue.  Potential subjects will be excluded if 
they are on medication which has a high clinical probability of drug interaction. Subjects will be 
provided with a list of drugs they should not take during the study. 
 
All serious adverse events will be sent to Dr. Natalie Murinova, the safety monitor, within 2 
business days. The safety monitor will evaluate how the event was handled by the study and 
make recommendations to the Principal Investigator on how procedures can be improved to 
further enhance patient safety. The safety monitor will have only safety-related responsibilities 
within the study. 
 
Subjects will be interviewed in private settings, will be counseled that they may refuse to answer 
any question, and will be reassured that the information they provide is confidential. 
 

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We will take all the usual steps to protect the confidentiality of their personal information, 
including but not limited to dissociating identifying information from research data; using unique 
alpha-number coding systems that permit linkages to identifying data only via files that are 
stored separately; storage of data on password protected servers or computers; storage of paper 
data forms in locked files within locked rooms with access limited to approved research staff; 
storage of audiotapes on a secure server with highly restricted password access and periodic 
download to permanent storage in locked facilities. All investigators and research staff are 
required to undergo HIPAA training and to sign a confidentiality agreement under the authority 
of the Human Subjects Division of the University of Washington. 
 
When a diagnosable condition such as major depression is detected, we will assess for potential 
suicidality. If the patient does not indicate current suicidal ideation, we will discuss immediately 
with the psychologist (Dr. Hoffman) or physician (Drs. Bell and Lucas) and an appropriate 
referral will be made. In the case of suicidality, we will use suicide management protocols that 
have are approved by our Institutional Review Board and include specific algorithms to assess 
risk, use of local Crisis Clinic numbers and 24/7 back-up by MD or PhD staff who can conduct 
more comprehensive assessments and make referrals as needed.  (See Appendix for Emergent 
Problem Protocol). 
Potential benefit of the study: Study participants may benefit from improvement in headache 
pain, associated symptoms and a decrease in disability following the use of study drug. Weekly 
telephone calls and the utilization of a headache diary may provide greater insight into their 
headaches. Potential societal benefits include decreased work loss and increased productivity, 

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decrease in loss of social interactions, and improvement in quality of life following the use of 
study drug.  
XVII. 
 Study Finances 
Funding Source 
This study is financed through a grant from the National Institute on Disability and Rehabilitation 
Research. 
Conflict of Interest 
All Study Principal Investigators and Key Personnel identified on the Study must file an initial 
COI disclosure with the University of Washington Office of Research by completing a form that 
captures disclosures of financial support and interests in several categories, including interests of 
a spouse or other immediate family member relative to the study; the aim is to provide the broadest 
and most comprehensive disclosure possible, while still respecting the Individual’s right to 
privacy. Subsequent COI disclosures must be filed annually until the end of the study, at the 
conclusion of the study, and one year following the end of the study. 
 Subject Stipends or Payments 
The subjects will be reimbursed $25.00 per clinic visit to honor their time and defray any costs. 
XVIII. 
 Overall Project Evaluation 
Overall study data completeness, timeliness, and quality will be monitored by Leslie 
Kempthorne in conjunction with Jeanne Hoffman, PhD.  Automated data reports will be 
generated monthly, displaying information relevant to the milestones described in the previous 
section. For example, cumulative subject accrual rates, subject retention rates, inter-rater 
reliability, and data accuracy reports will be generated routinely to monitor progress toward 

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goals. Progress toward study milestone will be discussed at the project meetings.  Quarterly 
reports will be filed with the NIDRR project officer.  Quarterly safety reports will be submitted 
to Dr. Murinova. 
 
If problems arise or tasks are not progressing as planned, Dr. Hoffman will work with the 
research team to devise an action plan.  Plans will be put in writing with a timeline to correct the 
problem.  Research Project Coordinator, Leslie Kempthorne, will track and follow-up on these 
plans. Any significant problems that would affect overall project outcomes will be reviewed with 
the NIDRR project officer to obtain additional assistance in developing an action plan.   
 
 

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Table 4.  Performance measures 
 
 
Performance Area 
Goal 
Review 
Schedule 
Evaluation 
Method 
Accountability* 
Pre Enrollment Activities 
Manual of Procedures 
3-2013 
Y1: Q2 
Ready for IRB 
Hoffman  
IRB Submission 
3-2013 
Y1: Q2 
IRB approval 
Hoffman, Glorieux 
Database  complete 
4-2013 
Y1: Q3 
Trial data entry 
Barber 
Pharmacy set-up 
4-2013 
Y1: Q3 
Protocol 
Glorieux 
Research Assistant 
trained 
5-2013 
Y1: Q3 
Observation of test 
administration and 
scoring 
Dikmen 
Study Binders and 
Patient Instruction 
Material 
4-2013 
 
 
Lucas, Glorieux 
Post-Enrollment Activities 
Enrollment per month 
2 per month 
Begin Y1: 
Q3, Monthly 
Enrollment report 
Hoffman 
Completion of 
baseline assessments 
95% 
Monthly 
Review by PI, Data 
Report 
Glorieux, Hoffman 
Completion of clinic 
visits/FU assessments 
95% 
Monthly 
Review by PI, Data 
Report 
Glorieux, Hoffman 
Completion of telephone 
FU calls 
95% 
Quarterly 
Review by PI, Data 
Report 
Glorieux, Hoffman 
Data Safety Monitoring 
100% 
Quarterly and 
as needed 
Review by PI, 
Quarterly report to 
Medical Monitor 
Hoffman, Murinova 
Data audit 
95% 
agreement 
Quarterly 
Rescoring and coding 
of 5% of assessments 
Hoffman, Temkin, 
Barber 
Data Analysis/Dissemination 
Complete primary report 
of study 
1-2017 
 
Submission of 
manuscript for review 
Hoffman, et al 
Design multi-center RCT 
May 2017 
 
Submission of grant 
proposal 
Hoffman, et al 
 
 
 

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Figure 4:   Project Staff Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Jeanne Hoffman, Ph. D.. 
Rehabilitation Medicine 
Principal Investigator 
Data Collection 
 
Taylor Obata 
Research Assistant 
Safety and Monitoring 
 
Natalia Murinova, M.D. 
Neurology 
Data Safety Monitor 
Executive Committee/  
Co-Investigators 
 
Sylvia Lucas, M.D., Ph.D. 
Neurology 
Protocol, Medical 
Sureyya Dikmen, Ph.D. 
Rehabilitation Medicine 
Training, Data Quality 
 
Nancy Temkin, Ph.D. 
Neurological Surgery 
Biostatistician 
 
 
Leslie Kempthorne, B.S. 
Project Coordinator 
 
Data Management 
 
Leslie Kempthorne, 
B.S. 
Project Coordinator 
 
Jason Barber, M.S. 
Data Analyst 
Neurological Surgery 
 

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TIMELINE 
Table 5: Anticipated Timeline for Sumatriptan Study 
 
Y1 
Y2 
Y3 
Y4 
Y5 
Pre-Enrollment Activities 
IRB Approval 
                    
Completion of Manual of Procedures 
                    
Headache Diary Application Development                     
Pharmacy Set-up 
                    
Staff Training 
                    
Enrollment Activities 
Enrollment 
                    
Intervention 
                    
Outcome Assessment 
                    
Post-Enrollment Activities 
Data Clean Up 
                    
Data Analysis 
                    
Primary Publication 
                    
Phase III Study Application 
                    
 
 
 
 

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