TENACITY: TelemEdiciNe-bAsed Cognitive Therapy for Migraine
Phase: NA
Conditions: Migraine Headache
Sponsor: VA Office of Research and Development

Title 
Telemedicine-based Cognitive Behavioral Therapy (TENACITY) for Veterans with Chronic 
Migraine: Study protocol of a pilot randomized controlled trial  
Trial registration 
ClinicalTrials.gov: NCT04613362 
Trial registration: data set 
Protocol version September 30, 2022 
Funding 
Veterans Health Administration VA Health Services Research and Development  
HSRD IRP 20-002 
Roles and responsibilities: contributorship 
Teresa M Damush, PI 
Samantha M Calcatera, Project Coordinator 
Elizabeth K Seng, Migraine Behavioral Treatment and Research Consultant 
Brenda T Fenton, Co-I 
Mindy Flanagan, Statistician 
Olivia Datre, Research Assistant 
Haley Lindsey, Research Assistant 
Charles Austin, Project Manager 
Emily Schlitz, Site PI 
Lea Eubanks, Interventionist 
Doyle Yuan, Site PI 
Stanley Taylor, Data Manager 
John Ney, Co-I, Health Economist 
Jason J Sico, Site PI, Headache Neurologist 
Amy S Grinberg, Co-I, Manualized treatment development and Interventionist 
 
 
Roles and responsibilities: sponsor contact information  
Roles and responsibilities: sponsor and funder 
 
Roles and responsibilities: committees 
 

Introduction 
Background and Rationale 
1. Description of research question and justification for undertaking the trial, including 
summary of relevant studies (published and unpublished) examining benefits and harms for 
each intervention 
 
Individuals with chronic migraine routinely face barriers that limit their access to evidence-
based (EB) behavioral headache treatment. With the Veterans Health Administration (VHA) 
infrastructure dedicated to efficient telehealth delivery into patient homes, the delivery of a 
behavioral intervention for headache (HA) via the telehealth platform is primed to address 
barriers of in-person care delivery and holds considerable promise to reach and reduce Veteran 
patients’ headache days. 
 
An evidence base of over 300 studies addressing behavioral headache interventions has exerted 
a substantive influence on contemporary headache pain management.(Rains, Penzien, McCrory, 
& Gray, 2005) Behavioral treatments have consistently been shown to be significantly more 
effective than control conditions and yield clinically-meaningful benefit,(Campbell & Penzien, 
2000) and have been found to be similarly efficacious to preventive pharmacotherapy,(Holroyd 
et al., 2001; Holroyd & Penzien, 1990; Powers et al., 2013) leading numerous professional 
practice organizations to recommend behavioral headache treatments as front-line 
interventions for chronic migraine (CM). For example, drawing upon evidence from an Agency 
for Healthcare Research and Quality (AHRQ)-funded meta-analysis(Goslin et al., 1999), the U.S. 
Headache Consortium, a multidisciplinary assemblage of seven professional organizations 
including the American Headache Society,(Silberstein & Consortium, 2000) recommended use of 
cognitive behavioral therapy (CBT) for CM.(Campbell & Penzien, 2000) Thus, the efficacy and 
value of behavioral headache interventions has been unequivocally demonstrated—their effect 
sizes are comparable to pharmacotherapy, the observed improvements are durable, they are 
essentially free of adverse events, and their use is strongly endorsed by multiple headache 
medicine stakeholders.  
 
Despite strong empirical support and endorsement by professional practice organizations, 
behavioral interventions are not widely available to headache patients. (Penzien, Irby, 
Smitherman, Rains, & Houle, 2015)Even when trained practitioners are available, clinic-based 
behavioral treatments remain inaccessible to many, given time restraints for patients. 
Considerable effort has been devoted to making behavioral headache therapies more accessible 
through development of limited therapist-contact formats (3-5 clinic appointments). Self-
management skills are introduced in clinic by a therapist, whereas skills-training occurs at home. 
This research suggests behavioral self-management interventions for headache can prove highly 
beneficial if delivered in a compelling format designed to enhance patients’ sustained 
engagement, thereby reducing treatment attrition. Despite the burgeoning empirical evidence 
that a broad variety of interventions are efficiently and effectively delivered via telemedicine 
approaches, this strategy has not yet been empirically studied for headache pain management. 
Therefore, we aim to implement and test a telemedicine-based delivery of CBT for CM 
employing our manualized migraine treatment protocol.  
 
Background and rationale: choice of comparators 
 

TENACITY’s manualized CBT sessions are adaptable through the delivery medium (telehealth vs 
in person), by number of sessions, and by the clinical role of the interventionists. The EHUT 
comparator was chosen to allow each site the flexibility of delivering an appropriate behavioral 
therapy(Grinberg et al., 2023) alternative.  
 
Objectives 
The objective of this study is to conduct a pilot randomized controlled trial (RCT) and determine 
the feasibility of the implementation of a cognitive behavioral therapy (CBT-HA) protocol for 
headache delivered via telemedicine (TENACITY) compared to enhanced headache usual 
treatment (EHUT).  
 
The investigators will recruit Veterans diagnosed with chronic migraine during the one-year 
recruitment period across the 3 VAMCs. The investigators will randomize eligible Veterans to 
participate either in the TENACITY intervention (n=50) or treatment as usual (n=50).                                
 
The specific aims are threefold: 
Aim 1: To develop a bundle of evidence-based practice (EBP) implementation strategies to 
engage 3 VA Medical Centers [2 Headache Centers of Excellence HCoEs and 1 general neurology 
service] and facilitate their local adaptation and implementation of Cognitive Behavioral 
Therapy (CBT) (TENACITY) through the vehicle of telehealth services.  
                
Aim 2. To conduct a pilot RCT and determine the preliminary efficacy and feasibility of TENACITY 
compared to TAU across 3 VA sites. We will conduct a superiority analysis. 
 
Hypothesis 2: Veterans receiving TENACITY will experience a statistically significant reduction in 
routine clinical headache metrics: headache frequency [headache days per month] (primary 
outcome), headache-related impairment and psychological symptoms (secondary outcomes) 
compared to enhanced headache usual treatment at 3 and 6 months. 
                             
Aim 3: The investigators will conduct exploratory cost analysis of TENACITY from the Veteran's 
perspective, using inputs from the pilot RCT, and a two-year budget impact analysis from the 
VHA's perspective, incorporating the costs of implementation as well as direct costs (and cost-
savings,) of providing the TENACITY intervention over all HCoEs to VHA.  
 
Hypothesis 3: TENACITY will be cost-effective and provide value to Veterans and VHA. 
 
 
Trial Design 
 
TENACITY is a single-blind, randomized, controlled, pilot trial with a single intervention arm and 
an enhanced headache usual treatment (EHUT) control arm analyzed as intention-to-treat. This 
multi-site study has a 31-day run-in/screening period to confirm chronic migraine and an 
approximately 12-week treatment period. Follow-up assessments are conducted at 3 and 6 
months post-treatment initiation.  
 

Methods: Participants, interventions, and outcomes 
Study Setting 
 
Participants will be recruited from three geographically distinct VA medical centers. Site one 
hosts a large, multidisciplinary HCoE, and is neurology-led with a strong health psychology 
program. Site two hosts a smaller VA Headache Consortium Center, is neurology-led, and has a 
developing health psychology program. Site three has no established HCoE and is a large-volume 
site with no health psychology program for headache. 
 
All study procedures will be conducted via telehealth, with no in-person, face-to-face 
communication. 
 
Eligibility Criteria 
 
Inclusion criteria. Veteran participants within the VHA medical system with an ICD-10 diagnosis 
of chronic migraine who complete at least 28 days of headache diary at baseline with a 
confirmed frequency of ≥8 headache days per month at baseline are eligible for this study.  
 
Exclusion criteria. Veteran patients with any of the following diagnoses are ineligible for this 
study: post-traumatic headache, cluster headache, other primary headache, post-whiplash 
headache, and trigeminal autonomic cephalalgia diagnosis. Also excluded are participants who 
have received ≥ 90 days opioid therapy from the date of chart screening; have a current 
diagnosis of severe cognitive impairment indicated by Short Portable Mental Status 
Questionnaire (SPMSQ); have a diagnosis of traumatic brain injury ≤ 1 year before diagnosis of 
chronic migraine or worsening of chronic migraine as indicated by post-traumatic headache 
screening tool; suffer from a disabling psychiatric illness (as noted by clinician); have had a 
psychiatric hospitalization in the last 6 months; relate daily suicidal ideation within the last 2 
weeks as indicated by the PHQ-9 with an answer of “3” to question nine; have severe 
depression, as indicated by PHQ-9 score ≥ 20; are terminally ill (life expectancy of <12 months as 
noted by clinician); decline to or cannot use the Annie App; have been treated by a HCoE clinical 
health psychologist in last two years. 
 
Interventionists: Two clinical psychologists employed by 2 of the 3 VAMCs trained to deliver CBT 
for Headache manualized behavioral treatment will provide the intervention. One of the 
psychologists will provide a telehealth clinic to the third site (VAMC) which is without any clinical 
psychologist trained in CBT-HA in addition to the local site. The two psychologists met to 
coordinate the treatment protocol prior to the start of the intervention.  
 
Interventions: description 
 
The TENACITY intervention consists of protocolled, manualized, short-term cognitive behavioral 
therapy for headache (CBT-HA) sessions which are administered via a telehealth delivery 
platform. Each session is approximately 50 minutes and follows a similar structure: (1) agenda 
setting (2) home practice check-in (3) learning a new skill (4) goal setting for home practice. The 
treatment will be delivered over approximately six biweekly sessions.(Grinberg et al., 2023)  
 

The enhanced headache usual treatment (EHUT) intervention consists of a referral to behavioral 
pain therapy contingent on the specific site. The therapies available are cognitive behavioral 
therapy for chronic pain (CBT-CP), integrated pain mindfulness, and dialectical behavioral 
therapy. Depending on which format is offered at the specific site, these therapies will be 
delivered either individually or in a telehealth group setting. 
 
Interventions will be initiated after patient randomization and subsequent scheduling with the 
appropriate clinician using the VHA clinical scheduler. Treatment will be administered using the 
VA telehealth platform, VA Video Connect (VVC) and/or telephone in one to one clinical visits.  
 
Interventions: modifications 
i. 
Criteria for discontinuing or modifying allocated interventions for a given trial 
participant (eg, drug dose change in response to harms, participant request, or 
improving / worsening disease) 
 
Treatment length and content is able to be modified and adjusted based on clinician discretion 
and mutual agreement with the participants.   
 
Interventions: adherence 
i. 
Strategies to improve adherence to intervention protocols, and any procedures for 
monitoring adherence (eg, drug tablet return; laboratory tests) 
 
Clinicians have the option of scheduling participants for subsequent sessions ahead of time to 
potentially improve adherence. Post-hoc chart abstractions will be conducted to assess 
intervention adherence.  
 
Interventions: concomitant care 
 
i. 
Relevant concomitant care and interventions that are permitted or prohibited 
during the trial 
 
There is no prohibited concomitant care during the course of the study. Participants will be 
asked to continue their usual medical headache care.  
Outcomes 
 
The primary outcome to be evaluated is change in the number of self-reported headache days 
during the past 31 days at 3 months compared to baseline. This outcome is considered the gold 
standard for prospective migraine research. 
 
Secondary outcomes include the change in headache-related impairment and psychological 
symptoms at 3 and 6 months compared to baseline. These include a battery of well-validated 
health questionnaires of functioning and symptoms that are tracked as part of routine headache 
care services both in VA and non-VA healthcare systems and include the following: Migraine-
Specific Quality of Life Questionnaire (MSQ); MIDAS; Headache-specific Pain Catastrophizing 
Scale (HPCS); Headache Management Self-Efficacy Scale (HMSE); Post Traumatic Stress Disorder 
(PCl-5); PHQ-9; GAD-7; Veterans RAND VR-12; Insomnia Severity Index (ISI). 
  

Participant timeline 
i. 
Time schedule of enrolment, interventions (including any run-ins and washouts), 
assessments, and visits for participants. A schematic diagram is highly 
recommended (see Figure) 
 
Upon enrollment, participants will begin a run-in period of a 31-day electronic headache diary.  
Participants will be asked to participate in a baseline interview and to complete health 
questionnaires. On completion of baseline headache diary, if all inclusion criteria are met, 
participants will be randomized to either CBT-HA (TENACITY) or EHUT. Consults will be placed to 
the appropriate clinical providers, with clinics contacting participants to schedule treatment. 
Participants will complete the 31-day headache diary and health questionnaires again at 
approximately 3 and 6 months after treatment initiation, along with an additional treatment 
satisfaction survey.  
 
 
 
Sample size 
i. 
Estimated number of participants needed to achieve study objectives and how it 
was determined, including clinical and statistical assumptions supporting any 
sample size calculations 

 
We will recruit Veterans until we have reached 100 eligible participants across the three VAMCs. 
We will randomize eligible Veterans to participate either in the TENACITY intervention (n=50) or 
enhanced headache usual treatment (EHUT) which may include outpatient clinic-based health 
psychology (n=50). This is a pilot feasibility demonstration to provide preliminary efficacy. The 
sample size estimate was based upon the staff resources available to screen, invite and recruit 
patients to reach 100 subjects over a 15-month period.  
 
Recruitment 
i. 
Strategies for achieving adequate participant enrolment to reach target 
sample size 
 
This study will recruit participants from three geographically distinct VA medical centers. All 
recruitment procedures will be conducted via phone, with no in-person communication, which 
will allow for greater reach to include entire VAMC catchment areas and eliminate any potential 
barriers due to COVID. 
 
Potential participants will be identified by either direct referral from a clinician or from a HCoE-
generated recruitment list which utilizes the VHA Headache Data cohort(Sico et al., 2022). The 
cohort is constructed using VHA electronic clinical and administrative data for Veterans with a 
headache diagnosis. Research staff will review each Veteran’s electronic health record in order 
to determine if they meet study inclusion criteria. If inclusion criteria are met, the Veteran is 
sent a recruitment letter by mail which describes patient incentives for participation ($25) per 
assessment period and will receive a follow-up phone call. During the phone call, research staff 
will provide a study overview and conduct further screening if the Veteran indicates interest.  
Methods: Assignment of interventions (for controlled trials)  
 
Allocation: sequence generation 
 
i. 
Method of generating the allocation sequence (eg, computer-generated random numbers), 
and list of any factors for stratification. To reduce predictability of a random sequence, 
details of any planned restriction (eg, blocking) should be provided in a separate document 
that is unavailable to those who enroll participants or assign interventions 
 
We will use a computer-generated random assignment stratified by 3 sites with no blocking. 
 
Allocation concealment mechanism 
i. 
Mechanism of implementing the allocation sequence (eg, central telephone; sequentially 
numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until 
interventions are assigned  
 
We will use a password protected computer file to conceal random assignment. 
Allocation: implementation 
i. 
Who will generate the allocation sequence, who will enroll participants, and who will assign 
participants to interventions 
 

Program manager will designate the random assignment upon participant completion of the 
baseline assessment and notify the respective clinical program and schedulers to contact 
the participants for their respective treatments. 
 
 
 
Blinding (masking) 
 
A TENACITY protocol evaluation will be conducted with participants at approximately 3 months 
post-treatment initiation in order to evaluate the study arms and exercises used in treatment. 
To protect research personnel blindness, the research staff member who is responsible for 
randomization will be the sole staff member to conduct these evaluations and collect self-
reported medical care received during the prior 3 months.  
 
Blinding (masking): emergency unblinding 
i. 
If blinded, circumstances under which unblinding is permissible, and procedure for 
revealing a participant’s allocated intervention during the trial 
 
Methods: Data collection, management, and analysis 
 
 
Data collection plan 
i. 
Plans for assessment and collection of outcome, baseline, and other trial data, including any 
related processes to promote data quality (eg, duplicate measurements, training of 
assessors) and a description of study instruments (eg, questionnaires, laboratory tests) 
along with their reliability and validity, if known. Reference to where data collection forms 
can be found, if not in the protocol  
 
Participants will complete a baseline interview and health questionnaires via phone or 
electronically using VA Qualtrics.  They will be assigned a 31-day headache diary using VA Annie 
app. Research staff will obtain Veteran permission to audio-record the interviews. Each 
interview will be recorded and transcribed. The health questionnaires and headache diary will 
also be completed at 3-month and 6-month post-treatment initiation, along with a treatment 
satisfaction survey.  
 
At the end of the 31-day run-in period, the participants will be contacted by phone to review the 
headache diary. If the participant self-reported ≥8 headache days over the course of the prior 31 
days and completed the first question of the headache diary on at least 28 days, s/he will 
remain eligible for the study. If the participant did not meet these criteria, they will be invited to 
complete an additional 31 days of headache diary, with the same stipulations applied. If they 
choose not to complete the headache diary a second time, they will be considered ineligible, 
removed from the study and sent back to the HCoE clinical provider to review other treatment 
options. Participants enrolled in the study will then be randomized to either the TENACITY arm 
or the EHUT control arm of the study.  
 

Screening Assessments 
Short Portable Mental Status Questionnaire (SPMSQ)  
The SPMSQ(Pfeiffer, 1975) will be utilized to screen potential participants for cognitive 
impairment. The SPMSQ is a 10-item measure with scoring guidelines as follows: intact 
intellectual functioning (0-2), mild intellectual impairment (3-4), moderate intellectual 
impairment (5-7), and severe intellectual impairment (8-10).  
 
American Migraine Study/American Migraine Prevalence and Prevention (AMS/AMPP) 
Diagnostic Module 
The AMS/AMPP will be utilized to assess Veterans for chronic migraine according to 
International Classification of Headache Disorders (ICHD-2) criteria. Respondents meet 
criteria for chronic migraine if at least 2 of 4 pain features are scored as a 3 or more, and 
nausea or both photophobia and phonophobia are scored 3 or more. The AMS/AMPP 
has a sensitivity of 91% and specificity of 80% for CM diagnosis.(Lipton, Diamond, Reed, 
Diamond, & Stewart, 2001)  
 
Post-Traumatic Headache (PTH) Screener  
The PTH will be utilized to determine if the participant meets criteria for post-traumatic 
headache.  
 
Patient Health Questionnaire (PHQ-9) 
The PHQ-9(Kroenke, Spitzer, & Williams, 2001) is a reliable and well-validated self-
report measure of depressive symptom severity and suicide risk based on Diagnostic 
and Statistical Manual of Mental Disorders (DSM) criteria. Items are rated from 0 to 3 (0 
= not at all, 3 = nearly every day). Total scores range from 0 to 27. Totals are categorized 
as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), 
and severe (20-27). Daily suicidal ideation is indicated by a response of “3” to question 
nine.  
 
Primary Outcomes Collection 
 
Reduction of headache days in the 31 days prior to the 3-month post-start of treatment mark is 
the primary outcome; reduction in headache days in the 30 days prior to the 6-month post-start 
of treatment mark will allow for measurement of cumulative benefit and persistence of efficacy.  
 
The VA Annie mobile application (Saleem et al., 2020) will be utilized as the platform for a daily 
headache diary. A protocol has been designed (Table 1) to send daily automated text messages 
to each participant for a total of 31 consecutive days. Participant responses are stored in the 
Annie system and are accessible by study staff. If a participant responds that they had a 
headache, eight additional questions are asked as indicated in Table 1. After being prompted 
with an Annie question, if the participant does not respond, a reminder message is sent every 
twenty minutes, with a maximum of three reminders per question.  
 
 
 
 
 

Q Text 
Response Options 
Action 
1 
Hello, it’s Annie. Did you have a headache today? 
Yes – HA 2 
No – HA 1 
If HA 2 → Q2 
If HA 1 → Q9 
2 
On a scale from 0-10, with 0=none and 10=worst, how 
severe was the headache?  
PN 0 – PN 10 
If response → Q3 
3 
Was the pain worse on one side of your head? 
Yes – SD 2 
No – SD 1 
If response → Q4 
4 
Was the pain pounding/throbbing? 
Yes – PD 2 
No – PD 1 
If response → Q5 
5 
Did light bother you? 
Yes – LT 2 
No – LT 1 
If response → Q6 
6 
Did sound bother you? 
Yes – SO 2 
No – SO 1 
If response → Q7 
7 
Did you feel nauseated or sick to your stomach or vomit? 
Yes – VO 2 
No – VO 1 
If response → Q8 
8 
Was the pain made worse with routine activities such as 
walking or climbing stairs? 
Yes – MV 2 
No – MV 1 
If response → Q9 
9 
On a scale from 0-10, with 0=none and 10=worst, how 
much did the headache interfere with your life today? 
IN 0 – IN 10 
 
 
Secondary Outcomes Collection 
Migraine Disability Assessment (MIDAS) 
The MIDAS(Stewart, Lipton, Dowson, & Sawyer, 2001) is a 5-item, self-report measure of 
disability related to headache based on number of missed or significantly limited activity 
days due to headache in school or paid work, household work, and family, social, or 
leisure activities. Responses are categorized as follows: little or no disability (0-5), mild 
disability (6-10), moderate disability (11-20), and severe disability (21+).  
 
Patient Health Questionnaire (PHQ-9) 
The PHQ-9(Kroenke et al., 2001) is a reliable and well-validated self-report measure of 
depressive symptom severity and suicide risk based on Diagnostic and Statistical Manual 
of Mental Disorders (DSM) criteria. Items are rated from 0 to 3 (0 = not at all, 3 = nearly 
every day). Total scores range from 0 to 27. Totals are categorized as follows: none-
minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), and severe (20-
27). Daily suicidal ideation was indicated by a response of “3” to question nine.  
 
Generalized Anxiety Disorder Screener (GAD-7) 
The GAD-7(Spitzer, Kroenke, Williams, & Löwe, 2006) is a reliable and validated 7-item, 
self-report measure of anxiety. Items are rated from 0 to 3 (0 = not at all, 3 = nearly 
every day). Total scores range from 0 to 21 and are categorized as follows: none-
minimal (0-4), mild (5-9), moderate (10-14), and severe (15-21) anxious symptoms. 
 
Post-Traumatic Stress Disorder Checklist (PCL)  
The PCL(Blevins, Weathers, Davis, Witte, & Domino, 2015) is a validated 17-item, self-
report measure of PTSD symptoms based on DSM criteria. Items are rated from 0 to 4 (0 
= not at all, 4 = extremely). Total scores range from 17-85.  Higher scores indicate higher 
post-traumatic stress symptoms. This measure was only collected at baseline. 

 
Insomnia Severity Index (ISI)  
The ISI(Bastien, Vallières, & Morin, 2001; Morin, Belleville, Bélanger, & Ivers, 2011) is a 
5-item measure of the respondent’s perceptions of their insomnia, such as severity of 
sleep-onset and sleep maintenance difficulties. Items are rated from 0 to 4 (0 = not at 
all, 4 = very much). Total scores range from 0 to 28. Totals are categorized as follows: no 
clinically significant insomnia (0-7), subthreshold insomnia (8-14), clinical insomnia 
(moderately severe) (15-21), clinical insomnia (severe) (22-28). The ISI has 
demonstrated good reliability and validity, particularly in detecting changes in perceived 
insomnia.  
 
Headache Pain Catastrophizing Scale (HPCS) 
The HPCS(Sullivan, 1995; Wheeler, Williams, & Morley, 2019) is a modified version of 
the validated Pain Catastrophizing Scale (substitutes “headache” for “pain” in the 
questions). The HPCS is a 13-item measure used to assess catastrophic thinking related 
to headache with three subscales: rumination, magnification, and helplessness. Item 
responses range from 0 to 4 (0 = not at all, 4 = all the time). Total scores range from 0 to 
52, with higher scores indicating higher levels of catastrophizing. A total score of 30 or 
higher indicates clinically significant catastrophizing.  
 
Headache Management Self-Efficacy Scale (HMSE)  
The HMSE(French et al., 2000) is a 25-item measure used to assess a respondent’s 
perception of their ability to take actions to prevent and manage their headaches and 
headache-related disability. Item responses range from 1 to 7 (1 = strongly disagree, 7 = 
strongly agree). Total scores range from 25 to 175 with higher scores indicating higher 
levels of headache management self-efficacy. The HMSE has demonstrated excellent 
reliability and construct validity.  
 
Veterans RAND-12 Health Status Inventory (VR-12)  
The VR-12(Selim et al., 2009) is a 12-item measure used to assess health related quality 
of life and to produce physical and mental health component scores.  
 
Migraine-Specific Quality of Life Questionnaire (MSQ)  
The MSQ(Martin et al., 2000) is a 14-item measure of headache-related quality of life 
with three dimension scores: role restrictive, role preventive, emotional. It has 
demonstrated evidence of construct validity and reliability.    
 
Data collection plan: retention 
i. 
Plans to promote participant retention and complete follow-up, including list of any 
outcome data to be collected for participants who discontinue or deviate from intervention 
protocols 
 
Participants will be eligible to receive a total of $150 in gift cards for completion of all data 
collection measures.  
 

Data management 
i. 
Plans for data entry, coding, security, and storage, including any related processes to 
promote data quality (eg, double data entry; range checks for data values). Reference to 
where details of data management procedures can be found, if not in the protocol 
 
Research staff will enter participant assessment data directly into a secure database. In 
addition, we will use a secure database (QUALTRICS) for participants to enter their self 
reported outcome data directly into a database. 
 
Statistics: outcomes 
i. 
Statistical methods for analysing primary and secondary outcomes. Reference to where 
other details of the statistical analysis plan can be found, if not in the protocol 
 
Analyses comparing the TENACITY and EHUT control groups on primary and secondary 
outcomes will be completed using linear mixed models for hierarchical and longitudinal data 
(patients are nested within site). The mediating and/or moderating effects of patient-level (e.g., 
age, gender, and depression) and facility-level variables will be examined.  
 
We will conduct an intention-to treat analysis. A generalized mixed effects model will evaluate 
the primary outcome of number of headache days and fixed effect of study arm, Visit (time) 
(Month 3 vs Baseline) and their interaction. Days will be clustered within Veteran and a first 
order autoregressive structure will be used for the relationship between adjacent days. 
 
Statistics: additional analyses 
i. 
Methods for any additional analyses (eg, subgroup and adjusted analyses) 
 
We will adjust for participant sex. 
 
Statistics: analysis population and missing data 
i. 
Definition of analysis population relating to protocol non-adherence (eg, as randomised 
analysis), and any statistical methods to handle missing data (eg, multiple imputation) 
 
We will evaluate missing data and will employ imputation for participants who complete at 
least 28 of 31 days of headache diary for our primary outcome. 
 
Methods: Monitoring  
 
Data monitoring: formal committee 
i. 
Composition of data monitoring committee (DMC); summary of its role and reporting 
structure; statement of whether it is independent from the sponsor and competing 
interests; and reference to where further details about its charter can be found, if not in the 
protocol. Alternatively, an explanation of why a DMC is not needed 
 
We have established a Data Safety Monitoring Committee that is comprised of two clinical 
psychologists employed by the VHA one of which is also a research scientist and an 

epidemiologist employed by VHA. This committee is independent from the sponsor and the 
research team. 
 
Data monitoring: interim analysis 
i. 
Description of any interim analyses and stopping guidelines, including who will have access 
to these interim results and make the final decision to terminate the trial 
 
No interim analysis will be conducted. 
 
Harms 
i. 
Plans for collecting, assessing, reporting, and managing solicited and spontaneously 
reported adverse events and other unintended effects of trial interventions or trial conduct 
 
Oversight for assessing potential harms or adverse events will be provided by Dr. Teresa 
Damush (PI) and co-investigator, Dr. Jason Sico MD, a board-certified headache specialist and 
Director of the West Haven VAMC Headache Center of Excellence, and Dr. Emily Lane Schlitz, a 
site PI and Dr. Doyle Yuan, a site PI .  
 
Research staff are trained to report any adverse events promptly to the PI and the project 
manager. Participants will be encouraged to report any adverse events they have experienced. 
We anticipate that using this active identification method will allow us to identify all adverse 
events in a timely manner.  
 
The project manager will be responsible for reviewing the adverse events reports of all 
participants each day, reporting the information to the PI, and if needed, reporting the adverse 
event to the IRB. As per VA policy, we will notify the IRB promptly using the appropriate form 
when a serious, study-related adverse event occurs. If the adverse event is serious, 
unanticipated or requires revision of the Project Description or Consent Form, we will notify the 
IRB by telephone as soon as possible and always within 24 hours. A formal report will be 
provided within 2 business days. All adverse events will be reported yearly to the IRB for review 
regardless of seriousness or relationship to the research. Because of this policy, the IRB will be 
providing parallel review of adverse events along with the PI. We believe this will ensure 
stringent oversight and early identification of any unexpected risks to human subjects. 
 
All adverse events will be monitored by the principal investigators and graded as “expected” or 
“unexpected” and graded for severity. All unexpected and serious adverse events will be 
reported to the IRB within 24 hours. Adverse events will be discussed and graded by the entire 
study team at the weekly team meetings.  
 
All study personnel will have access to community mental health contacts (local phone numbers, 
1-800 numbers) and will be trained on emergency plans for subjects found to be actively 
suicidal. All patients who have scores indicating depression diagnosis and who have not been 
diagnosed or treated will be advised to contact their primary care provider for evaluation. We 
will also contact the primary care providers of all undiagnosed/untreated subjects whose scores 
indicate severe depression and/or suicidality. 
 

Auditing 
i. 
Frequency and procedures for auditing trial conduct, if any, and whether the process will be 
independent from investigators and the sponsor  
 
This study is subject to triennial audits and any additional audits according to the policies of the 
local IRB at each study site.  
 
Ethics and dissemination 
 
 
Research ethics approval 
i. 
Plans for seeking research ethics committee / institutional review board (REC / IRB) approval 
 
Approval by local site ethics committees, IRBs, and R&D committees will be obtained prior to 
any study procedures taking place. Any relevant modifications to the study requiring review by 
these entities will be submitted and approved before implementing them.  
 
Protocol amendments 
 
i. 
Plans for communicating important protocol modifications (eg, changes to eligibility criteria, 
outcomes, analyses) to relevant parties (eg, investigators, REC / IRBs, trial participants, trial 
registries, journals, regulators) 
 
All protocol modifications will be agreed upon by investigators and submitted to the appropriate 
IRBs for approval. Should the modifications potentially affect a participant’s willingness to 
participate in the study, the modifications will be discussed with participants and an updated 
informed consent will be signed if applicable.  
 
Consent or assent 
i. 
Who will obtain informed consent or assent from potential trial participants or authorised 
surrogates, and how (see Item 32) 
 
Trained research staff will obtain consent from potential trial participants. Potential participants 
will be sent the following documents via mail or DocuSign: Informed Consent, HIPAA 
Authorization, Patient-facing health questionnaires, Headache Diary Script. Once the patient 
receives the documents, research staff will conduct a formal consent process via telephone. 
Dependent on individual IRB regulations, either verbal or written consent will be obtained.  
 
Consent or assent: ancillary studies 
i. 
Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies, if applicable 
 
Confidentiality 
i. 
How personal information about potential and enrolled participants will be collected, 
shared, and maintained in order to protect confidentiality before, during, and after the trial 
 
Identifiers will be removed from the identifiable private information that is collected. Research 
staff will treat personal information with professional standards of confidentiality. Study  

standard operating procedures for data collection and data management have been designed to 
protect against data loss and maintain patient confidentiality. Computer files will be password 
protected. Files containing names or other personal identifiers will have a separate password 
and will be accessible only to personnel who need to contact participants. Study data will be 
maintained on VHA network servers which are secured and backed-up on a nightly basis. Access 
to these servers is controlled by network administrators. There is little risk to loss of privacy or 
confidentiality given these measures, and there has been no instance of a problem in this area in 
prior trials conducted by this investigative team.  
 
Audio files will be stored on a password-protected, restricted-access server at the Richard L. 
Roudebush VA Medical Center, 1401 W. 10th Street, Indianapolis, Indiana 46202. All recording 
devices used for this study are encrypted for security and once the files are uploaded to the 
server, the files are deleted from the device. Recordings are then transferred to a VA-contracted 
transcription service where the recordings are transcribed or are transcribed by Indianapolis VA 
HSR&D center staff and cleaned of any information that would identify a participant. Each 
participant is assigned a unique study identification number at the time of enrolment. This will 
be the only identifier on the transcripts and research documents. Only research staff on this 
study will have access to the coding system. 
 
Research records will be maintained by the investigator in accordance with the VHA Records 
Control Schedule. Organizations that may inspect and/or copy your research records for quality 
assurance and data analysis include groups such as the investigator and his/her research 
associates, the study sponsor, the Indiana University Institutional Review Board or its designees, 
the VA Research and Development Committee’s designees, and federal agencies, including but 
not limited to the Office for Human Research Protections (OHRP), the Office of Research 
Oversight (ORO), VA Office of the Inspector General (OIG). A description of this clinical trial will 
be available on ClinicalTrials.gov, as required by U.S. law.  
 
Declaration of interests 
i. 
Financial and other competing interests for principal investigators for the overall trial and 
each study site 
 
There are no financial or competing interests for the principal investigator and at each site. 
Data access 
i. 
Statement of who will have access to the final trial dataset, and disclosure of contractual 
agreements that limit such access for investigators 
 
Information collected for this study may be used for future research studies or shared with 
other researchers for future research. If this happens, information which could identify 
participants will be removed before any information is shared.  
 
Ancillary and post trial care 
i. 
Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer 
harm from trial participation 
 
The VA medical facilities shall provide necessary medical treatment to a research subject injured 
as a result of participation in a research project approved by a VA Research and Development 

Committee and conducted under the supervision of one or more VA employees in accordance 
with applicable federal regulations (38 CFR 17.85). This does not apply to (1) treatment for 
injuries due to noncompliance by a subject with study procedures; or (2) research conducted for 
VA under a contract with an individual or a non-VA institution. Financial compensation for 
research-related injuries is not available.  
 
Dissemination policy: trial results  
i. 
Plans for investigators and sponsor to communicate trial results to participants, healthcare 
professionals, the public, and other relevant groups (eg, via publication, reporting in results 
databases, or other data sharing arrangements), including any publication restrictions 
 
The study team will disseminate results publicly through professional conferences and 
publications. 
 
Dissemination policy: authorship 
Authorship eligibility guidelines and any intended use of professional writers 
We will follow standard guidelines by professional publications for authorship eligibility. 
 
Dissemination policy: reproducible research 
 
i. 
Plans, if any, for granting public access to the full protocol, participant-level dataset, and 
statistical code 
 
Appendices 
 
 
Informed consent materials 
 
i. 
Model consent form and other related documentation given to participants is available 
upon request. 
 
 
 
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