Does Acceptance and Commitment Therapy (ACT) Improve Disability in Chronic Migraine? A Randomized Headache Center Trial
Phase: NA
Conditions: Chronic Migraine
Sponsor: Brigham and Women's Hospital

 
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Institutional Review Board 
Intervention/Interaction Detailed Protocol 
 
 
Principal Investigator: 
Paul Rizzoli, MD 
 
Project Title: 
Does Acceptance and Commitment Therapy (ACT) Improve Disability in 
Chronic Migraine? A Randomized Headache Center Trial 
 
Version Date: 
2024-11-26 
 
 
Version Name/Number: 
1.2 
 
 
 
1. 
 Background and Significance 
 
 
Chronic migraine prevalence is 3% of the migraine population (1), though the majority of 
patients seen in a headache center and is often a disabling condition. Pharmacologic 
management has expanded and improved in recent years though it nonetheless provides 
incomplete control in many patients. Even the best specialty headache clinic management falls 
short in providing relief to some chronic migraine patients. Behavioral therapies have shown 
efficacy in pain conditions, including migraine. Behavioral treatments may improve disability 
related to headache more so than headache days, a traditional measure of headache treatment 
efficacy. However, reduced disability is, in the end, the most important outcome in headache 
management. If behavioral management, in addition to usual treatment, can improve disability 
outcomes in patients, an argument can be made for expanding access to these modalities in the 
headache clinic setting. 
 
Acceptance & Commitment Therapy (ACT), often referred to as the “third wave of cognitive 
behavioral approaches,” has helped treat a variety of conditions, including depression, anxiety, 
and chronic non-headache pain. Mo’Tamedi and colleagues (2) performed a trial in which 
participants with chronic tension-type headache or CM were randomized to receive eight weekly 
sessions of ACT in addition to standard treatment or standard treatment only. After 8 weeks, 
participants reported improvement in disability, affective aspects of pain, and anxiety. More 
recently, Grazzi et al (3) demonstrated the positive effect of ACT in participants with high 
frequency migraine without aura and the benefit persisted at one year out. 
 
ACT departs from mainstream cognitive behavioral therapy approaches in a number of respects. 
The most unique aspect is learning to accept one's present condition (vs. the more typical 
approaches that focus on direct approaches for managing and coping with a given condition). The 
overarching aim of ACT-based therapies for pain is to promote greater psychological flexibility by 
cultivating six different positive psychological capacities: acceptance, defusion, mindfulness, 
sense of self, values, and committed actions.  

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Acceptance in ACT is not merely tolerance: rather, it is the active and nonjudgmental embracing 
of experiences in the here and now as they are. Mindfulness is one of the ways to increase 
acceptance, achieve cognitive defusion and thus increase behavioral flexibility. Studies have 
documented the effectiveness of ACT interventions for improving disability, lessening the impact 
of pain, and developing resilience for varied types of recurrent non-headache pain conditions and 
migraine. The latter finding is particularly important as individuals with low resilience, especially 
those currently experiencing chronic pain, are more susceptible to emotional difficulties when 
exposed to stressful situations and this, in turn, gives rise to conditions such as depression or 
anxiety. 
 
 Studies (4,5) examining the clinical utility of mindfulness and ACT in chronic pain conditions and 
migraine have demonstrated how these practices help by increasing pain tolerance, reducing the need 
for symptomatic medications, reducing the frequency of migraine attacks as well as the course of 
migraine episodes, and by modulating certain personality characteristics of patients with migraine, 
such as anxiety, rigidity, low acceptance, and low resilience. Patients with pain can be effectively 
supported by nonpharmacological approaches, such as ACT, to manage their pain and the anxiety 
connected to pain, by improving their clinical condition, and by decreasing the likelihood of a long-
term negative course. Specifically, patients with chronic migraine may benefit from attending ACT 
treatment not only in terms of clinical improvement, but also through reduction of the medication 
intake. The integration of ACT into standard care merits continued study, replication and extension to 
other sites to more fully identify both the strengths and limitations of this particular integrative 
approach 
 
 
 
2. 
Specific Aims and Objectives  
 
Hypothesis: The addition of Acceptance and Commitment Therapy to usual care will improve measures of 
disability in chronic migraine participants, as measured by the Headache Disability Index, comparing 
changes in scores from baseline to 3 months. Secondary and exploratory analyses are as noted. This is a 
single site randomized, open-label phase II pilot study. Participants will be randomized 1:1 with the 
following method using a computerized random generator into 2 groups: ACT and usual treatment. Initial 
ACT training requires 8 virtual group visits over 2 months. All participants will be assessed at 3, 6 and 12 
months. ACT training involves 8 one-hour sessions covering six different positive psychological capacities: 
acceptance, defusion, mindfulness, sense of self, values, and committed actions, followed by two review 
sessions. The goal of ACT is to improve mindfulness. Mindfulness is one of the ways to increase 
acceptance, achieve cognitive defusion and thus increase behavioral flexibility which should lead to 
reduced disability in the migraine population.  
 
Chronic migraine is a potentially disabling condition that requires medical management in most patients. 
Studying chronic migraine patients without the use of some form of standard or usual medical 
management would not be feasible. Restricting usual management would be unduly harsh and would 
limit recruitment. Thus, both groups will be offered usual or standard management. Conversely it seems 
clear that medical management is not a complete solution in many patients. Though many patients 
improve with usual treatment, many still report some level of disability. This study tests the hypothesis 
that ACT can improve reported disability in these patients. 
 

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As above, the expected improvement in disability justifies the intervention with ACT. ACT typically 
requires some training. Though other, and shorter, protocols for training ACT may prove useful and should 
be investigated, in this study we continue the protocol that was shown useful in studies with other 
migraine participants (3). It is expected that all participants will undergo all training sessions, however, if 
a minimum # of 6 of 8 of the training sessions are completed, individual participation in the study can 
continue.  
 
A participant is considered to have completed the study if he or she has completed the baseline 
assessment, ACT training if so randomized and the 3-month, 6-month and 12-month follow-up 
assessments. Participants will be allowed to miss up to 2 sessions and miss 0 visits in order to continue in 
the study. 
 
 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Assessment of change in 
disability measure 
 
 
Change in the Headache Disability Index 
(HDI) from baseline to 3 months 
 
Scores at 3 months minus scores at baseline. 
Negative numbers indicate a higher 
reduction of headache-related disability 
 
The HDI has good 
psychometric 
properties, and gets at 
both emotion and role 
function disability well 
Secondary 
 
 
Assessment of disability 
measures at baseline, 3, 6, 
and 12 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of anxiety and 
depression at baseline, 3, 6, 
and 12 months 
 
Headache Disability Index (HDI) at baseline, 
3, 6, and 12 months 
25-item survey with total scores ranging 
from 0-100, with higher scores indicating 
higher levels of disability. 
 
Headache Impact Test (HIT-6) at baseline, 3, 
6, and 12 months 
36-78; <50 little impact, 50-55 some 
56-59 substantial, >59 severe 
 
Migraine Disability Assessment Score 
(MIDAS) at baseline, 3, 6, and 12 months0-
270; 0-5 little/ no disability, 
6-10 mild, 1-20 moderate, > 20 severe 
 
Hospital Anxiety and Depression Scale 
(HADS) at baseline, 3, 6, and 12 months 
All accepted and 
validated scales for 
their endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. 
General Description of Study Design 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
 
Assessment of catastrophic 
thinking related to headache 
at baseline, 3, 6, and 12 
months 
 
Assessment of mindfulness  
at baseline, 3, 6, and 12 
months 
 
 
 
2 scales, 0-21 each. 0-7 normal, 8-10 
borderline, >= 11 significant anxiety or 
depression 
 
Patient Catastrophizing Scale (PCS) at 
baseline, 3, 6, and 12 months0-52, >= 30 
significant catastrophizing 
 
 
Five Facet Mindfulness Questionnaire  
(FFMQ) at baseline, 3, 6, and 12 months 
39 items  
 
 
 
Tertiary/Exploratory  
 
 
Abortive Medication Use, as 
recorded by participants 
Headache Diary/ App in use daily by 
participants 
 
This is a standard 
measure 
- 
12-month open label study comparing two arms, participants 
with CM are randomly assigned to either usual treatment or 
usual treatment with ACT. Usual treatment is as managed by 
any provider in our headache center. ACT is a third wave 
behavioral treatment employed by patients superimposed on 
usual treatment after eight 1-hour weekly virtual group training 
sessions, conducted by research staff, to teach the modality. 
- 
Primary Objective: To compare impact on the chronic migraine 
population with and without treatment with ACT 
- 
Secondary Objectives: To assess other disability measures, the 
use of abortive medications, to assess work productivity and 
catastrophizing 
- 
Primary Endpoint: Change in Headache Disability Index (HDI) 
from baseline to 3 months. 

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Schedule of Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schema 
 
 
- 
Secondary Endpoints: HDI, HIT-6 for impact, MIDAS for 
disability, PCS, FFMQ and HADS at baseline, 3 months, 6 
months and 12 months. 
 
Pre-screening 
(Pre-consent) 
Telephone 
Contact to set 
up screening 
visit 
 
Baseline Visit 1 
Day 1 -
Screening/Enrol
8 virtual 
training visits 
for those 
randomized to 
ACT – see sched 
Visit 2 
About 3 mos 
after Visit 1
Visit 3 
 3 mos after  
Visit2 
Visit 4 
6 mos after V 3 
Completion 
EMR Review Eligibility 
X 
 
 
 
 
 
 
Informed Consent 
 
 
X 
 
 
 
 
Demographics 
 
 
X 
 
 
 
 
Clinical history 
 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Outcome Evaluation 
 
 
 
 
 
 
 
HDI 
 
 
X 
 
X 
X 
X 
HIT 6 
 
 
X 
 
X 
X 
X 
MIDAS 
 
 
X 
 
X 
X 
X 
PCS 
 
 
X 
 
X 
X 
X 
FFMQ 
 
 
X 
 
X 
X 
X 
Abortive medication use 
 
 
X 
 
X 
X 
X 
HADS 
 
 
X 
 
X 
X 
X 
Adverse Events Reporting 
 
 
 
 
X 
X 
X 
Total N: 40 
Pre-screen potential participants by inclusion and exclusion criteria; schedule Visit 

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4. 
Subject Selection 
 
Conduct informed consent process. Perform baseline assessments. 
 
See Section Error! Reference source not found., Schedule of Activities 
Randomize 
Group A 1-4 of 5 
pts each 
N = 20  
Group B 
N = 20  
Virtual Sessions 1-8 
over 2 months 
 
Usual Treatment 
Visit 2- One month 
after training 
completion 
Visit 2- 3 months 
after randomization 
Three months after Visit 2 
6 months after Visit 3 
Final Assessments 

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We anticipate screening 100 active headache center participants, through referral of clinic providers, in 
order to reach the target enrollment size of 40 participants over two months.  
 
Subject selection will be from those patients referred to us by providers in the headache center. Providers 
will be made aware that the study is recruiting and provided details of the study in written form. Under 
the prep to research provision, the referring provider will do the following in this process:  
• 
discuss with the patient that there is a study for which they may qualify or be interested;  
• 
communicate the name of the study and the PI;  
• 
get verbal permission to provide their contact information to our study team;  
• 
once permission is obtained, the referring provider will share the contact information with our 
research team securely.  
 
Prior to calling those from whom permission was obtained, we will verify preliminary eligibility in the 
medical records (e.g., chronic migraine diagnosis) under a partial waiver of HIPAA. If we determine they 
are eligible, potential participants will then be contacted by phone or other preferred method of contact 
discuss the project.  
 
Information collected under the HIPAA waivers, for recruitment purposes, of patients who either are not 
eligible or elect not to join the study will be destroyed as soon as possible.  
 
   
 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Stated willingness and ability to engage in the consent process 
2. Stated willingness to participate in the study, despite randomization outcome 
3. Availability for the duration of the study  
4. Males and females; Age 18-65 
5. Diagnosis of chronic migraine, with or without medication overuse, and followed in the Graham 
Headache Center. 
6. Access to necessary resources for participating in a technology-based intervention (i.e., virtual 
training visits) 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Known major depression or other psychiatric condition as reported in the clinical 
documentation 
2. Non-English speaking since meetings are interactive, in English, and translation is not possible. 
3. Secondary headache diagnosis as reported in the clinical documentation 
4. Any psychotherapy in the prior 18 months 
5. Any reason which the treating provider feels would limit the participant’s ability to learn or 
practice ACT 
6. Previous experience with mindfulness or meditation approaches (lifetime) 
 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently assigned to the study intervention or entered in the study. Individuals who do not meet the 

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criteria for participation in this trial (screen failure) because of meeting one or more exclusion criteria that 
are likely to change over time may be rescreened. Examples include the successful treatment of a previous 
affective disorder, and the lifting of physical activity restrictions previously in place.  
 
 
5. 
Subject Enrollment 
 
Subject screening and enrollment will take place after pre-screening. The screening visit will take about 
30 minutes. It can be completed by phone or in person. Institutional email, or Patient Gateway, may be 
used only to schedule visits. During the visit, we will discuss the purpose of the study, review the consent 
form and address any questions and review and sign the consent form in person or by phone using 
econsent in REDCap. Screening and enrollment may be followed by a waiting period of up to several 
weeks, to allow enough participants to be enrolled to create a training group (this will be explained during 
the consent process).  
 
6. 
STUDY PROCEDURES 
 
After the consent process is completed, the participant will be randomized to group A or B and 
questionnaries will be administered.  
 
We anticipate 3-4 training groups of 5 participants each. Intervention attendance will be monitored and 
recorded (e.g., via role call).  Failure to attend more than 2 sessions in 8 weeks will result in removal from 
the study. Makeup sessions may be offered when possible. Training is conducted by a physician 
experienced in the procedure and is based on a prior published protocol (3). 
 
The intervention will be completed virtually through use of an MGB instance of Zoom. No in-person 
offerings are anticipated. The intervention will be done by a study team psychologist trained in the use of 
ACT. Each session has a theme as noted in the included training documents. Intervention sessions will not 
be recorded. Subjects may interact during the training meetings. Subjects will be addresses through use 
of first names only. No other identifiers will be provided. Before each session the study team will ask 
participants to ensure they are in a private location. 
 
No regular email communication is anticipated apart from scheduling information provided to the 
subjects. 
 
Initial randomization is as per the study description. This is an open-label trial.Patients will be randomized 
to receive either ACT or usual treatment. Randomization will use a permuted block method (7). The 
randomization ratio will be 1:1. A biostatistician will generate the randomization codes and upload the 
randomization list in the Redcap system. 
 
In addition, participants will maintain daily diaries on paper and this data will be collected periodically. 
These will be used to measure abortive medication intake and practice times. 
 
Regular, daily or near-daily, practice of mindfulness both during and after the intervention sessions will 
be encouraged. Practice may be recorded in the daily diaries that participants are encouraged to maintain. 

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In addition, participants are provided two audio practice guidance recordings, one of 3 minutes in length 
and one of 12 minutes in length to help guide practice. 
 
For this protocol, participants may use non-opioid analgesics for pain control, including over-the-counter 
medications and dietary supplements, and prescribed medications as per the recommendations of their 
provider, i.e. usual treatment. Abortive medication usage will be assessed at each study visit and 
documented in the relevant Case Report Form (CRF).  
 
When a subject discontinues from ACT but not from the study, remaining study procedures will be 
completed as indicated by the study protocol.  If a clinically significant finding is identified (including, but 
not limited to changes from baseline) after enrollment, the investigator or qualified designee will 
determine if any change in participant management is needed. Any new clinically relevant finding will be 
reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for 
determining the need to discontinue 
• 
If the participant is due to complete assessments within 2 weeks of being discontinued from the 
study intervention, those assessments will be administered at the time of discontinuation; if the next 
scheduled assessments are more than 2 weeks from the discontinuation date, the discontinued 
participant will wait for the next scheduled assessment. Thereafter, the participant will be included in all 
future scheduled assessments, even though not participating in the intervention. 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance 
• 
Lost-to-follow up; unable to contact subject (see Section Error! Reference source not found., Lost 
to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up  
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are discontinued from the 
study will not be replaced. 
 
A participant will be considered lost to follow-up if he or she fails to return for one scheduled visit and 
study staff are unable to contact the participant after at least 3 attempts.  
 

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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
• 
The site will attempt to contact the participant, reschedule the missed visit within 2 weeks, 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts will be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up 
 
Study procedures as per the Schedule of Activities, include questionnaires as below and the recording of 
diary information, along with assessment of any adverse events: 
Data will be maintained in a secure fashion as described elsewhere in the protocol. 
No specific provision is allowed for transmittal of specific questionnaire results to participants since 
individual scores are not likely to be of value to the participant. 
 
Compensation in the amount of $50.00 will be provided to each participant after the completion of each 
study timepoint (BL, 3m, 6m, 12m). If the participant completes the entire study the compensation will 
total $200.00. 
 
 
 
7. 
Risks and Discomforts 
 
There are no known risks to therapy with ACT.  
ACT is evidence-based and effective, and generally considered to be free of side effects. Nevertheless not 
all participants are good candidates for ACT. For participants with rooted trauma, for example, ACT may 
be not enough to meet their needs; moreover, as ACT sessions include many reflections, exercises and 
abstract concepts, participants with psychiatric problems may not be good candidates for this approach. 
ACT is also not suitable for participants who have difficulty linking discussions and insights for the different 
sessions since often such participants are not able to perform the exercises on their own. The training is 
fairly extensive, 8 hours over 2 months, and this could stress participants’ schedules. We will remind 
participants of the voluntary nature of the research. 
 
Loss of confidentiality is a risk related to the collection of protected health information and study data for 
this project. We will miminize these risks by using MGB REDCap and implementing other confidentiatily 
procedrues outlined in the confidentiality section below.  
Loss of privacy is a risk related to study participation, including the virtual intervention. To mimimize this 
risk, the intervention will be conducted through the use of a secure MGB Zoom program. All participants 
will be reminded to minimize the disclosure of personal information while in the session; sessions will not 
be recorded; and participants will be asked to ensure they are in a private location where they feel 
comfortable participating and others cannot hear them (or the meeting in general); the use of headphones 
may be appropriate for some participants to protect the privacy of other participants. 
 

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Email communication will be conducted using send secure or permission will be obtained if unencrypted 
email is preferred, before emailing, and will be limited to meeting scheduling information.  
 
8. 
Benefits 
 
ACT theorizes that our thoughts and perspectives are shaped by language, past experiences and our 
environment. ACT encourages patients to separate themselves from their framework of negative thoughts 
and beliefs. In ACT, psychological flexibility is the ability to live a full and meaningful life despite ongoing 
adversity. Research has shown that ACT is an effective form of treatment for medical and psychological 
conditions. The goal of ACT is not to reduce or eliminate symptoms. Instead, ACT helps patients reframe 
their thinking about their condition and life events, and live their life in the most fulfilling way possible 
The literature confirms links between stress and pain, and shows chronic pain to be a biopsychosocial 
condition, unlikely to be managed fully by medications alone. The increase of medication intake to face 
up to a chronic pain condition can increase the risk of medication overuse and addiction. ACT can help 
patients to tolerate and manage symptoms by reducing medication intake, promoting and encouraging a 
more holistic definition of wellness including acceptance of negative experiences, integrating negative 
emotions and learning to manage them. Metaphors and paradoxes are applied in ACT to support patients’ 
understanding of the related concepts. Benefits have been demonstrated but in the short and long term 
in patients suffering from anxiety disorders, chronic pain conditions and migraine. The integration of ACT 
into standard care merits continued study and replication to more fully identify both the strengths and 
limitations of this particular integrative approach, which might be useful for reducing the risk of long-term 
development of CM associated with medication overuse headache. 
 
 
9. 
Statistical Analysis 
 
We expect that mean reduction in HDI scores from baseline to 3 months will be larger in the ACT 
treatment group compared to the usual treatment group among the subject with chronic migraine. 
 
Based on the published study (4), we expect the participants will have an average baseline HDI of 51.4 ± 
19.0. Seng et al.’s study observed a larger decrease in mean HDI score of 14.3 points from baseline to 4 
months in the Mindfulness-Based Cognitive Therapy group compared to the usual care group (0.2 points 
reduction). Our proposed sample size of 40 participants (20 participants each group) will allow us to 
observe an 18.1 ± 19.0-point reduction in the ACT group from baseline to month 3 and a 0.2 ± 19.0-point 
reduction in the usual treatment group, with 80% power and a two-sided alpha of 5%. An 18.1-point 
reduction (35% from the baseline) is larger than the reported study. However, Jacobson et al.’s study 
suggested that a change in the HDI score of 29 points or more could be used to assess the efficacy of 
headache management strategies (8). Considering those two studies, we chose our effect estimate of 18.1 
reduction for our ACT group. There is no reported standard deviation of change in HDI. For the purpose 
of the calculation, the standard deviation of 19.0 from the baseline value was utilized. Our proposed 
sample size of 40 participants will include a loss of follow-up of 10%.  
 
All randomized subjects will be included in the Intention to Treat (ITT) analysis.  
 
All numerical primary and secondary outcomes will be summarized using descriptive statistics (N, Mean, 
Standard Deviation, Minimum, and Maximum) at baseline, month 3, month 6, month 12, a difference 

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from baseline to month 3, a difference from baseline to month 6, and a difference from baseline to month 
12, stratified by treatment group.  
 
The change in HDI from baseline to 3 months will be calculated by subtracting the HDI at baseline from 
the HDI at 3 months. We will use a Student’s test to assess the change from baseline to 3 months in HDI. 
We will check distributions of the change in HDI before we apply Student’s t-test. If the data has non-
normal distribution, we will apply Wilcoxon Rank Sum test. Treatment group will be tested at a 2-sided 
5% significance level. All efforts will be made to collect the participants’ HDI data at each visit. If we have 
missing baseline or 3 months HDI data, the subjects will be list wise deleted from the primary analysis. 
 
The longitudinal secondary endpoints (HDI, HIT-6, MIDAS, HADS, PCS and FFMQ) will be presented 
graphically and numerically.  The analysis will use a restricted maximum likelihood-based repeated 
measures approach with a random slope and intercept model.  Visit will be analyzed as days since 
randomization. The analysis will include the fixed, categorical effect of treatment group, fixed continuous 
effect of visit, and the treatment group-by-visit interaction. The baseline value will be included as a fixed 
covariate.  Random effects will be included for participant response and for both visit and intercept.  An 
unstructured covariance structure will be used to model the within-participant errors.  If this analysis fails 
to converge, the other structures that will be tested will include spatial power because visits are unevenly 
spaced, and compound symmetry. The covariance structure converging to the best fit, as determined by 
Akaike’s information criterion, will be used.   The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom and adjust standard errors.  The analysis will use all measurements 
obtained over the 12-month study period, including those from patients who had discontinued study.  The 
model allows for missing data assuming missing at random.   Significance tests will be based on least 
squares means using a two-sided α = 0.05 with two-sided 95% confidence interval. The primary treatment 
comparison of slopes will be assessed through the treatment-by-visit interaction coefficient. Assumptions 
for models will be assessed by examining plots of the residual values. 
 
We will examine all adverse events (AEs) and serious adverse events (SAE) by the type of event, as well as 
by body system class. We will report number of AEs and SAEs stratified by treatment group.  
 
Baseline demographic or clinical characteristics will be summarized using descriptive statistics (N, Mean, 
Standard Deviation, Minimum, and Maximum for numerical characteristics and N and percentage for 
categorical characteristics). The summary will be stratified by treatment group.  
 
There are no planned interim analyses. There is no planned sub-group analyses. There are no planned 
exploratory analyses. 
 
 
 
10.   Monitoring and Quality Assurance 
 
 
This protocol uses the definition of adverse event from 21 CFR 312.32 (a): any untoward medical 
occurrence associated with the use of an intervention in humans, whether or not considered intervention-
related. 

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For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will 
be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
All adverse events (AEs) will have their relationship to study procedures, including the intervention, 
assessed by an appropriately-trained clinician based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
• 
Related – The AE is known to occur with the study procedures, there is a reasonable possibility 
that the study procedures caused the AE, or there is a temporal relationship between the study 
procedures and the event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study procedures and the AE. 
• 
Not Related – There is not a reasonable possibility that the study procedures caused the event, 
there is no temporal relationship between the study procedures and event onset, or an alternate 
etiology has been established. 
 
A clinician with appropriate expertise in Headache Medicine will be responsible for determining whether 
an adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously described for the 
study procedures. 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study will be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 

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The clinical research coordinator will record events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
In consultation with the PI, a trained member of the study team will be responsible for conducting an 
evaluation of a serious adverse event and shall report the results of such evaluation to the NIH and the 
reviewing Institutional Review Board (IRB) as soon as possible, but in no event later than 10 working days 
after the investigator first learns of the event. 
 
 
 
11. Data and Research Material Sharing 
 
Data collection will be the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant consented/enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents will be consistent with the data recorded on the 
source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into <specify name of data capture system>, a 21 CFR 
Part 11-compliant data capture system provided by the <specify Data Coordinating Center>. The data 
system includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents. 
 
 
Sending Data/Materials to Research Collaborators outside Mass General 
Brigham 
 
NA 
 
Receiving Data/Materials from Research Collaborators outside Mass General 
Brigham 
 

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NA 
 
12. Privacy and Confidentiality 
 
☒ Study procedures will be conducted in a private setting. 
☒ Only data and/or specimens necessary for the conduct of the study will be collected. 
☒ Data collected (paper and/or electronic) will be maintained in a secure location with appropriate 
protections such as password protection, encryption, physical security measures (locked 
files/areas) 
☐ Specimens collected will be maintained in a secure location with appropriate protections (e.g. 
locked storage spaces, laboratory areas) 
☒ Data and specimens will only be shared with individuals who are members of the IRB-approved 
research team or approved for sharing as described in this IRB protocol. 
☒  Data and/or specimens requiring transportation from one location or electronic space to 
another will be transported only in a secure manner (e.g. encrypted files, password protection, 
using chain-of-custody procedures, etc.) 
☒   All electronic communication with participants will comply with Mass General Brigham secure 
communication policies. 
☒ Identifiers will be coded or removed as soon as feasible and access to files linking identifiers 
with coded data or specimens will be limited to the minimal necessary members of the research 
team required to conduct the research. 
☒ All staff are trained on and will follow the Mass General Brigham policies and procedures for 
maintaining appropriate confidentiality of research data and specimens. 
☒ The PI will ensure that all staff implement and follow any Research Information Service Office 
(RISO) requirements for this research. 
☐ Additional privacy and/or confidentiality protections 
 
 
13.   References 
 
1. Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the 
United States: Updated age, sex, and socioeconomic-specific estimates from government health 
surveys. Headache. 2021 Jan;61(1):60-68.  
2. Mo’tamedi H, Rezaiemaram P, Tavallaie A. The effectiveness of a group-based acceptance and 
commitment additive therapy on rehabilitation of female outpatients with chronic headache: 
preliminary findings reducing 3 dimensions of headache impact. Headache. 2012;52:1106-1119. 
3. Grazzi L, Bernstein C, Raggi A, Sansone E, Grignani E, Searl M, Rizzoli P. ACT for migraine: effect 
of acceptance and commitment therapy (ACT) for high-frequency episodic migraine without 
aura: preliminary data of a phase-II, multicentric, randomized, open-label study. Neurol Sci. 
2019 May;40(Suppl 1):191-192.  
4. Seng EK, Singer AB, Metts C, Grinberg AS, Patel ZS, Marzouk M, Rosenberg L, Day M, Minen MT, 
Lipton RB, Buse DC. Does Mindfulness-Based Cognitive Therapy for Migraine Reduce Migraine-
Related Disability in People with Episodic and Chronic Migraine? A Phase 2b Pilot Randomized 
Clinical Trial. Headache. 2019 Oct;59(9):1448-1467.  
5. Grazzi L, D'Amico D, Guastafierro E, Demichelis G, Erbetta A, Fedeli D, Nigri A, Ciusani E, Barbara 
C, Raggi A. Efficacy of mindfulness added to treatment as usual in patients with chronic migraine 

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and medication overuse headache: a phase-III single-blind randomized-controlled trial (the 
MIND-CM study). J Headache Pain. 2023 Jul 14;24(1):86.  
6. Pocock S: Clinical Trials: A Practical Approach. New York: John Wiley; 1984. 
7. Jacobson GP, Ramadan NM, Aggarwal SK, Newman CW. The Henry Ford Hospital Headache 
Disability Inventory (HDI). Neurology. 1994 May;44(5):837-42.