RELAXaHEAD for Headache Patients (Phase II): RELAXaHEAD for Migraine and Sleep
Phase: NA
Conditions: Migraine, Headache, Multiple Sclerosis, Insomnia
Sponsor: NYU Langone Health

 
 
Official Title: 
RELAXaHEAD for Headache Patients (Phase II): RELAXaHEAD for 
Migraine and Sleep   
NCT Number: 
NCT05466682 
Study Number: 
17-00525-2 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
July 14, 2022 
 
 

 
1 
 
P u r p o s e o f t h e S t u d y 
Headaches are extremely common; migraine is the 6th most disabling condition per the World Health 
Organization (WHO). Post traumatic headache is one of the most common symptoms after a concussion. Prior 
research has shown that Progressive Muscle Relaxation Therapy (PMR) is an effective treatment for headache 
patients 1,2. PMR is a simple, easily taught,3,4, fairly safe .1 but under-utilized behavioral treatment. 5,6 Prior 
research demonstrates that pain self-management training increases self-efficacy and self-management 
behaviors while improving pain and depression outcomes.7 
Traditionally, psychologists have introduced PMR to patients. However, physicians have difficulty 
finding providers and patients have difficulty accessing and paying for behavioral treatments for chronic 
pain conditions such as for migraine.8-10 
To address these limitations smart-phone based implementations of PMR have been developed by 
our group and others. The long-term goal of 
this research is to assess the utility of 
smartphone-based PMR for the treatment of 
headaches. While there are many commercially 
available electronic diary and MBI apps for 
headache, there is little data showing their 
efficacy.11,12 Our RELAXaHEAD 
app incorporates the electronic PMR that was 
successfully used in an earlier epilepsy study13 
and beta tested with headache specialist and 
migraine patient input. It also has functionality to 
track medications. We plan to conduct a 2-arm randomized controlled study to evaluate the feasibility and 
acceptability of RELAX for use with headache patients. One arm will be the RELAX group (the RELAXaHEAD 
app) and the other arm will be a monitored usual care (MUC) group (this group receives standard of care and 
uses the electronic daily symptom reporting diary). The goals are to assess the feasibility and adherence of 
the RELAX intervention in persons with headache (Aim 1) and to gather data on the effects of the RELAX 
intervention on headache disability (Aim 2). 
Aim 1: Conduct a feasibility and acceptability study of the RELAX approach in migraine and post- 
traumatic headache (PTH) patients who visit the NYU Department of Neurology General Practice and/or 
subspecialty groups or the NYU Concussion Center. We will recruit and randomize subjects (N=400) in the 
FGP Neurology Group including the MS Center and Headache Center and the NYU Concussion Center to 
receive the RELAX intervention or monitored usual care (MUC). Both groups will be asked to complete daily 
diaries, and data will also be collected on measures of recruitment, retention, adherence, and satisfaction with 
the PMR, the clinically important endpoint. With the PMR, we hypothesize that at least 70% of participants will 
be adherers (e.g., use RELAXaHEAD at least 4 days/week for 12 weeks). We will assess if the daily diary is 
acceptable by examining whether there is differential attrition with daily diary completion. We hypothesize no 
difference between the two groups for acceptability of the diary. We will define acceptability as an average 
score of ≥4 (0-5 Likert scale) on the 9-item acceptability questionnaire.14 The outcomes for Aim 1 are the 
feasibility/acceptability outcomes; number of days of diary entered, number of days of pmr, time spent/day on 
pmr (Please refer to Table 2) 
Aim 2: Conduct within group analyses of the RELAX approach vs MUC.                         
Affective  
Increased 
Perceived 
Risk 
                  
 
Acquisition of  
Knowledge  
(about 
pharmacologic 
treatment  
options) and  
skills 
Behavioral 
change  
(progressive 
muscle 
relaxation 
therapy) 
PI: Mia Minen, MD, MPH 
Version Date: 6.28.2022 
Study Number: s17-00525 
Title: RELAXaHEAD for Headache 
Patients 
Response 
Cuein 
g 
Redefined 
Self-concept 

 
2 
In the migraine patient population, the primary outcome will be migraine quality of life and migraine disability 
measured by Migraine Quality of Life (MSQ) and the MIDAS. In the migraine-MS population, a primary 
outcome will also be MS pain related disability as measured by the MOS Pain Effects Scale (PES). 15 
Secondary outcomes include headache frequency and intensity, stress levels, sleep and psychiatric screens 
(NIH PROMIS depression and anxiety screens). We hypothesize that at 3 months compared with baseline 
there will be trends in the RELAX arm towards decreased disability (as measured by the Migraine Disability 
Assessment Scale (MIDAS)) and improvements in MS pain related quality of life in the MS-migraine patient 
population. 
   In the PTH patient population, we will examine the secondary outcomes noted above. 
B a c k g r o u n d 
Research indicates that behavioral therapies e.g., progressive muscle relaxation (PMR), cognitive 
behavioral therapy (CBT), and biofeedback are effective treatments for a wide range of conditions and are 
effectively free of adverse effects.1 They have have enduring benefits 16 and may be less costly than 
pharmacologic interventions.17 However, these behavioral treatments have not traditionally been 
implemented in outpatient neurology settings or medical settings such as primary care or obgyn where 
patients often present for care. Smartphone-based, electronically delivered behavioral interventions might 
be ideal interventions for testing in the neurology outpatient setting (and perhaps other outpatient settings 
where migraine patients present for care) because they are portable and do not require specialist 
intervention. 
PMR has Grade A evidence for migraine prevention and has also been show to be effective in 
other headache disorders. 1 Research has already shown that prudent limited office treatment (PLOT), 
not just traditional clinic-based behavioral treatment programs, can reduce the frequency and intensity of 
migraine for up to 6 months. 18,19 Long-term, PLOT is more cost effective than traditional clinically based 
treatments and many preventive pharmacologic treatments.20,21 In this proposal, we study the feasibility 
and acceptability of providing headache patients in the outpatient setting with electronically delivered PMR, 
a standardized, evidence-based behavioral treatment used for migraine since the 1980s.22,23 We selected 
PMR as the behavioral intervention because of its success as a technique that patients can do 
independently.3,4 For example, in the Stress Management in Living with Epilepsy (SMILE) study, 13 in a 
written communication with Dr. Sheryl Haut (December 2016), PMR was successfully delivered using a 
smartphone app. Preliminary daily diary adherence was around 85%. We have modelled our 
RELAXaHEAD app after the app used in the SMILE study. The RELAXaHEAD app has the same PMR as 
in the SMILE study but also includes a daily pain diary. Our RELAXaHEAD app has backend analytics 
built-in to record the amount of time spent playing the PMR. Pain intensity, duration, stress levels, mood, 
sleep, and medications taken can be recorded using the app. In addition, the RELAXaHEAD app allows 
the use of reminders and timely follow-up of non-compliant participants via real time investigator data 
monitoring capabilities. The RELAXaHEAD application was developed by IRODY and NYUMC MCIT 
previously approved its development. It is the previously unnamed app in the IRB study s16-00548. 
Most migraineurs who present for care are between ages 18 and 50 years, and >80% of Americans in 
this age group have smartphones.24 Migraine patients can successfully use smartphone applications. Both 
patients and researchers prefer smartphone apps with electronic headache diaries— a reliable 
method for data collection and more discreet than paper diaries,25 with fewer secondary data errors,26 less 
administrative burden,27,28 high participant acceptance,28 and potential cost savings.29 Additionally, 
researchers prefer this format because it allows the use of reminders and timely follow-up of non- adherent 
participants via real time investigator data monitoring capabilities. Currently, Over 100 commercial 
headache applications are currently available, and many of these apps claim various purposes, including 
the ability to treat headaches with behavioral therapies. However, limited data exist on whether the 
smartphone applications with behavioral therapies for chronic pain conditions, like migraine, are feasible 
and acceptable. 12 

 
3 
S t u d y D e s i g n 
F r o m t h i s p o i n t f o r w a r d , p a t i e n t s a r e r e f e r r e d t o a s “ s u b j e c t s ” i f t h e y 
a g r e e d t o e n r o l l i n t h e s t u d y . 
Subjects will be recruited from the New York University Medical Center (NYUMC) FGP neurology practice*, 
urgent care practices and from the FGP primary care practices in addition to the private practice of Dr. Audrey 
Halpern (who is a private practice neurologist who is affiliated with NYU). Screening will be done as follows: 
All methods will be done as below except for the following exceptions outlined below: 
Main method: With help from the EPIC research data team, we will generate an appropriate report to identify 
potential subjects that may be contacted. These are people who are age 18-80 with a diagnosis of “headache” 
who were seen at NYU within the past 6 months. The report will flag those who have opted out of being 
contacting about research at NYU and the epic research team will delete such patients before sending us the 
report. Within the Department of Neurology, all locations will be notified by the department’s leadership that 
recruitment of their patients may take place unless there is objection on the provider’s part. 
Exceptions: 
Dr. Audrey Halpern’s Office: Dr. Halpern does not use EPIC. She will approach her own patients to inquire 
about participation in the study. 
Neurology Urgent Care Practice: At this time, there is no epic code listed as part of the Neurology Urgent Care 
visits so an epic report cannot be generated as in the cases above. However, the Neurology FGP maintains a 
list of the patients seen through the Neurology Urgent Care Practice. On a weekly basis, this list will be sent by 
a FGP administrator to the epic research team and the patients will be screened based on the study eligibility as 
described in the irb (diagnosis of “headache” and age 18-80). If these patients meet study eligibility and have 
not opted out of being contacted for research purposes, then they will be forwarded to Dr. Minen’s research 
team. The Epic data lists will be generated weekly and potential subjects will be screened and contacted on a 
near daily basis. A record will be made in RedCap, a HIPAA compliant database, using de-identified info for all 
those who screen in and those who screen out. For those who screen in and decide to enroll in the study, an 
identified record will be created in RedCap. 
We had recruited participants who had called the NYU Concussion Center. However, recruitment for this arm of 
the study is closed at this time. We had also recruited patients with Multiple Sclerosis and headache and 
recruitment has closed at this time. 
Screening will be done by IRB approved members of the study team. This includes both paid staff and NYU 
nontraditional volunteers. 
The NYU Headache Research Program has been recognized for its solid training of pre-health students in 
research methods. In fact, it received the first ever City College of New York S Jay Levy Fellowship for Future 
Leaders Distinguished Internship Site Host Award (2017-2018). 
We carefully select from a group of specially selected group of CUNY students who are part of the highly 
coveted S Jay Levy Fellowship. These students are pre-selected by CUNY for their professionalism and top 
grades and then the students undergo a very selective interview process by Dr. Minen. We also take high 
achieving Barnard students who are pre-health who have high grades and many of whom are part of the 
Barnard Summer Research Institute. Dr. Minen has been a mentor as part of this program for several years, and 
the students in this program are supposed to learn research methods from start to finish, culminating in a poster 
presentation at a minimum. We have attached a copy of the training curriculum to this protocol based on the 
training that was done last year. In brief, the students take the online CITI training and pre-read selected articles 
prior to the on-site training. Then, there are four full days of one-site training led by Dr. Minen the first week 

 
4 
f oll o w e d b y a n a d diti o n al w e e k of s h a d o wi n g t h e alr e a d y tr ai n e d r e s e ar c h t e a m. Dr. Mi n e n t h e n o b s er v e s e a c h 
st u d e nt t h e s e c o n d w e e k wit h a p arti ci p a nt t o e n s ur e tr e at m e nt fi d elit y.  
All st u d y t e a m m e m b er s will h a v e u n d er g o n e a o n e w e e k tr ai ni n g i nt e n si v e t o u n d er st a n d t h e s cr e e ni n g pr o c e s s  
, r e cr uit m e nt pr o c e s s, i nf or m e d c o n s e nt pr o c e s s a n d e nr oll m e nt pr o c e s s ( a s d e s cri b e d t hr o u g h o ut t hi s I R B). I n 
bri ef, r e s e ar c h v ol u nt e er s will b e tr ai n e d d uri n g a n i nt e n s e o n e w e e k tr ai ni n g o n st u d y pr o c e d ur e s i n cl u di n g a n 
e m p h a si s o n h o w t o s cr e e n, r e cr uit, c o n s e nt, a n d e nr oll t h e p arti ci p a nt s. T hi s i s a n o ri s k/ v er y l o w r i s k st u d y 
u nli k e ot h er i nt er v e nti o n al st u di e s. It i s si mil ar t o m a n y of t h e h u n dr e d s of c o m m er ci al a p p s a v ail a bl e o n t h e 
m ar k et t h at p e o pl e u s e e v er y d a y. T h u s, it i s a p pr o pri at e f or tr ai n e d r e s e ar c h v ol u nt e er s t o c o n s e nt t h e s e 
p arti ci p a nt s j u st a s t h e y w o ul d b e a bl e t o d o s o f or s ur v e y t y p e st u di e s. T h e y st u d y t e a m m e m b er s will b e 
c ar ef ull y o b s er v e d d uri n g t h e i niti al c o n s e nt pr o c e s s t o e n s ur e t h at t h e y ar e d oi n g it c orr e ctl y.  
W e h a v e I R B a p pr o v e d s cri pt s/ m e s s a g e s t h at will b e u s e d f or c o nt a cti n g p ot e nti al  p arti ci p a nt s. A n a d diti o n al 
o n e w a s cr e at e d f or t h e F G P ur g e nt c ar e p arti ci p a nt s. W e al s o h a v e I R B a p pr o v e d s cri pt s f or c o m m u ni c ati n g 
wit h pr o vi d er s.  
W e will u s e eit h er u s e a p h o n e s cri pt t o r e cr uit p ot e nti al s u bj e ct s f or t h e st u d y or e m ail s cri pt vi a N Y U  HI P A A 
c o m pli a nt e m ail, H e a d a c h e R e s e ar c h @ n y u m c. or g or R E D C a p.  
T h e t ot al N will b e 4 9 0. W e h a d a n i niti al a p pr o v al f or N = 4 0 2. G oi n g f or w ar d, w e ar e h o pi n g t o r e cr uit a n 
a d diti o n al 9 0 s u bj e ct s fr o m t h e F G P Ur g e nt C ar e C e nt er a n d fr o m t h e N e ur ol o g y Ur g e nt C ar e C e nt er.  
 
T h e i niti al st at s w er e c al c ul at e d a s f oll o w s:  
S a m pl e si z e: P h a s e 1: 4 3 2 s u bj e ct s, P h a s e 2: 9 0 s u bj e ct s  
P h a s e 1: T h e N C CI H u s e s t h e Kr a m er r ef er e n c e f or p o w er c al c ul ati o n. A s i n di c at e d b y Kr a e m er a n d 
c oll e a g u e s, o ur pil ot s a m pl e si z e ( 4 0 2) i s b a s e d o n t h e pr a g m ati c s of r e cr uit m e nt a n d t h e r e q ui sit e s f or 
e x a mi ni n g f e a si bilit y. W e a nti ci p at e a n a d h er e n c e r at e of at l e a st 7 0 %. If t h e a d h er e n c e r at e i s b el o w 5 0 %, w e 
will c o n si d er t h e a p pr o a c h i n n e e d of f urt h er r efi n e m e nt. T hirt y p ati e nt s p er ar m will all o w e sti m ati o n of a n e x a ct 
9 5 % c o nfi d e n c e i nt er v al w h o s e l o w er b o u n d e x c e e d s 5 0 %. T h er ef or e, i n s uffi ci e nt a d h er e n c e w o ul d b e r ul e d 
o ut, a s s u mi n g t h e tr u e a d h er e n c e r at e i s 7 0 % or gr e at er. T hi s a p pr o a c h o b vi at e s t h e n e e d t o h a n dl e mi s si n g 
d at a, b e c a u s e s u bj e ct s w h o dr o p o ut will b e a s s u m e d n o n -c o m pli a nt.  
T h u s, w e pl a n t o tr y t o e nr oll mi gr ai n e p ati e nt s fr o m t h e g e n er al n e ur ol o g y gr o u p, t h e N Y U H e a d a c h e s p e ci ali st s 
wit hi n t h e m ai n a c a d e mi c c e nt er ( 6 5 0 Fir st A v e n u e/ A C C), t h e N Y U H e a d a c h e C e nt er i n t h e M e n’ s H e alt h 
C e nt er a n d fr o m Dr. H al p er n’ s offi c e. W e w o ul d al s o li k e t o r e cr uit at M S S o ci et y e v e nt s a n d ot h er n e ur ol o g y 
e v e nt s.  
R e s e ar c h a s si st a nt s will e v al u at e w hi c h p ati e nt s ar e eli gi bl e t o p arti ci p at e b a s e d o n t h e i n cl u si o n a n d e x cl u si o n 
crit eri a st at e d b el o w.  
P h a s e 2: W e arri v e d at t h e 9 0 ur g e nt c ar e s u bj e ct s b a s e d o n o ur i niti al p o w er a n al y si s a n d t h e n t h e NI H’ s 
r e q u e st i n t h e J u st i n Ti m e t o i n cr e a s e t h e N u p t o 8 5. 
O ur i niti al s a m pl e si z e w a s j u stifi e d b a s e d o n t h e f e a si bilit y o ut c o m e of c o m pli a n c e wit h P M R a m o n g p ati e nt s i n 
t h e R E L A X gr o u p. W e a nti ci p at e d a n i niti al c o m pli a n c e r at e of at l e a st 7 5 %. T h e pl a n n e d s a m pl e si z e al s o 
pr o vi d e d a d e q u at e p o w er f or t h e pri m ar y e x pl or at or y o ut c o m e ( MI D A S fr o m b a s eli n e t o 3 m o nt h s) a n d t h e 
s e c o n d ar y o ut c o m e ( n u m b er of h e a d a c h e s/ 3 0 d a y s). C o n si d eri n g MI D A S a s t h e pri m ar y o ut c o m e c a n r e d u c e 
d at a s k e w e d n e s s a n d i m pr o v e st u d y p o w er. B a s e d o n t h e st u d y, t h e st a n d ar d d e vi ati o n ( S D) of MI D A S 
r a n g e s fr o m 5 t o 7. U si n g t h e c o n s er v ati v e e sti m at e of S D = 7, gr o u p s a m pl e si z e s of 3 0, wit h a nti ci p at e d 2 5 % 
dr o p o ut l e a di n g t o a p pr o xi m at el y 2 3 p ati e nt s p er gr o u p, a c hi e v e 8 0 % p o w er t o d et e ct a cli ni c all y si g nifi c a nt 
diff er e n c e of 5. 7 5 b et w e e n t h e gr o u p s, a s s u mi n g a si g nifi c a n c e l e v el of 0. 0 5 u si n g a t w o -si d e d t w o -s a m pl e t - 
t e st. 

 
5 
Subsequently, based on later data, we found that only about half of the participants have full follow-through so 
the 90 (similar to the NIH request) is more adequate for this. 
G e n d e r o f S u b j e c t s  
Both genders will be included. 
A g e o f S u b j e c t s 
18-80 (18 – 65 in urgent care) 
R a c i a l a n d E t h n i c O r i g i n No enrollment restrictions. 
I n c l u s i o n C r i t e r i a [ B o x 1 ] age 18–80;(18-65 in urgent 
care) 
Meets migraine criteria based on International Classification of  
Headache Disorders (ICHD) 3 beta (based on questions in  
REDCap), Migraine Disability Assessment (MIDAS) score >5. 4+ 
headache days a month. 
OR 
Meets Chronic PTH criteria based on International Classificationof  
Headache Disorders (ICHD) 3 beta (based on questions in 
REDCap) and had 4+ headache days a month, is 3-12 months post 
initial injury. 
OR  
Meets Insomnia criteria based on the Insomnia Severity Index (score > or = 15) 
E x c l u s i o n C r i t e r i a [ B o x 1 ] 
Patients who have had Cognitive Behavioral Therapy, 
Biofeedback or other Relaxation Therapy in the past year; Cognitive deficit or other physical problem with 
the potential to interfere with behavioral therapy; Alcohol or other substance abuse as determined by self-
report or prior documentation in the medical record; Opioid or barbiturate use 10+ days a month; Unable or 
unwilling to follow a treatment program that relies on written and audio recorded materials; Not having a 
smartphone  
V u l n e r a b l e S u b j e c t s 
N/A 
Methods & Procedures 
[Please note that Phase 1 is now complete-we are now in Phase 2 of the study] 
For phase 1 of the study, a single arm study was done to assess the feasibility and acceptability of the 
recruitment process and the app. The duration of this Phase was 6 months. The subjects were asked to use 
the application for at least 3 months. Compliance was checked during this time and compliance calls were 
done to remind the subject to use the application. In the latter 3 months we studied if the subjects continued to 
use the application on their own. 
July 2020: We are reopening the Phase 1 single arm study to assess the feasibility of virtual subject enrollment 
prior to expansion to a larger study. Phase 1 will be conducted as above with a N=30 subjects. The steps will 
Box 1: Inclusion Criteria: Age 18–80 years (age 
18-65 in urgent care); Meets migraine criteria 
based on the International Classification of 
Headache Disorders (ICHD) criteria; Migraine 
Disability Assessment (MIDAS) score >5. 4+ 
headache days a month.OR Meets Chronic  
PTH criteria based on International  
Classification of Headache Disorders (ICHD) 
criteria, is 3-12 months post-injury, and there 
are 4+ headache days a month. Scoring > or = 
15 on the ISI. Exclusion Criteria: Patients who 
have had Cognitive  
Behavioral Therapy, Biofeedback, or other 
Relaxation Therapy in the past year; Cognitive 
deficit or other physical problem with the 
potential to interfere with behavioral therapy; 
Alcohol or other substance abuse as 
determined by self-report or prior  
documentation in the medical record; Opioid or 
barbiturate use 10+ days a month; Unable or 
unwilling to follow a treatment program that 
relies on written and audio file materials; Not 
having a smartphone. 

 
6 
be the same as before but instead of coming for an in-person appointment, subjects will enroll via virtual 
sessions. Like before, the data is stored and can be viewed by the PI and study team online. In this iteration, 
subjects may contact the physician/the physician may contact the subject to discuss app data if s/he wants to 
discuss headache management as part of clinical care. This is intended to take the place of paper diaries 
which were used during in-office visits. 
Phase 2 of the study will be a two-arm randomized controlled trial (RCT) in the outpatient setting at NYULMC 
to assess feasibility and acceptability of the RELAX approach. The duration of Phase 2 is 3 months. We are 
beginning the urgent care RCT in May 2019. All patients will complete a migraine disability and migraine 
quality of life assessment and track their headache frequency and intensity using our RELAXaHEAD app. 
Data will be collected from the app and adherence will be reinforced with blinded telephone calls. Data 
collection on these outcomes are important to determine the user burden of data collection. The subjects will 
only use the application for an initial 60days based on the data we have to date (from Phase 1), and we will 
see if subjects continue to use the application during the third month. 
The physician / NTV will provide the open-enrollment card to potential subjects when they approach them 
about the study.  
Designated study team members will pre-screen patients in Epic as indicated elsewhere in the procedure using 
the Epic Research Report. They will obtain patient consent for the study. Once consented, patients will be 
randomized to RELAX or MUC. The study team member will then collect patients’ health histories and baseline 
data in REDCap on an iPad, download the app onto patients’ smartphones, and conduct the sessions (see 
below). Physicians listed as study staff on this protocol may also consent and enroll eligible patients if they 
note that one of the patients under his/her care is appropriate for the study. There is currently an Android 
version and an IOS version. In addition, we will use Data Core to locate potentially eligible patients with 
migraine within the NYU health system at NYU Langone and NYU Brooklyn sites from primary care and the 
various neurology divisions. These potential patients will be sent a message via MyChart. 
The designated study team members will be trained to use the scripted protocol and treatment manual. The first 
four sessions of each member will be audio-recorded to assess treatment fidelity. Afterwards, one out of every 
ten will be audio-recorded to assess treatment fidelity. 
If the study subject is in the RELAXaHEAD (Intervention) Group: The study team member will explain the 
rationale for PMR and load the RELAXaHEAD app onto the patients’ smartphones. 
Rationale (quoted from Smitherman T. and Penzien D. Headache: Advances in Psychotherapy 2014): 
“As we discussed earlier, physical changes in our bodies associated with stress and arousal can produce 
headaches. Oftentimes, people say they are relaxed but their body still has a lot of tension that they do not 
recognize. It is important for you to learn how to 1) prevent your body from becoming tense; 
2) recognize when your body becomes tense; and 3) truly relax your body and get rid of that tension. 
Relaxation will help you learn to control physical arousal and thus help prevent headaches. Research has 
shown that learning relaxation leads to fewer and less intense headaches for most migraineand tension- type 
headache patients so long as they regularly use and practice their skills. This relaxation training program is 
going to teach you a specific set of procedures—not just ‘trying to relax’ on your own. You will learn to tense 
and then release various muscle groups throughout your body, step-by- step. By tensing your muscles first 
you can notice how different it feels to be truly relaxed. Over time you will be able to relax very quickly in 
almost any situation. Becoming skilled at relaxation will give you increased control over stress-related 
biological changes that cause headaches, and relaxation often produces many other positive changes.” 

 
7 
PMR: The RA or RV will explain the rationale for PMR and download the application onto the subject’s 
smartphones. The subject will perform PMR in the ED and discuss the optimal time and place to practice 
PMR at home.  
Subjects will also enter their headache log daily on the app. The APP will track the amount of time playing the 
PMR. Subjects will be asked to do the following: 
Intervention: 
Week 1: 5 min deep breathing at least 5/7 days of the week  
Week 2: 5 min PMR session at least 5/7 days of the week  
Week 3: 15 min pmr preferred at least 5/7 days of the week  
Week 4: pmr at least 4 days a week (optional body scan)  
Week 5: pmr at least 3 days a week (optional body scan) 
Weeks 6-8: use when it is most helpful (falling asleep, HA coming on, stress) 
The study intervention will be 8 weeks in duration but the full study length will be 6 months. There will be a 
baseline assessment (T0), a f/u call or email at one week (T1), a 30 day phone call or email assessment (T2), a 
60 day phone call/email (T3), and a 90 day phone call/email (T4) (to examine persistence of effect after a 
month). The last follow up will be at 6 months to examine persistence of effect 4 months after the intervention 
ends. As we learned previously, we are adding the option for email as some subjects prefer email. 
The MUC session is where the subjects are explained that in migraine treatment, they may be given 
medications to take to stop a migraine and medications to prevent a migraine. The mainstay of migraine 
management is a headache diary where people can track their headache days, headache intensity, medications 
taken, and any other details they think might be pertinent to share with their medical provider. No written 
material is provided during this session. 
MUC: To match the time spent with the designated study team member, subjects will be given a general 
education session consisting of basic migraine information, such as evidence-based ways to treat headaches:  
treat early, limit acute medications < 2–3 days/week, and call the primary care physician (PCP) if abortive 
medications are used more frequently. They will be shown a website:  
https://miachen26.wixsite.com/relaxahead (to be renamed).  The study team member will load the app onto the 
subject’s smartphone but the PMR component will be blocked on the version of the app that the MUC subject 
receives. 
All subjects will be asked to track headache frequency, intensity, and acute medication use on app. All subjects 
will get the post enrollment card after they have been enrolled so that they have some instructions on what to do 
when they go home. 
All subjects will receive written educational material about migraine.30 All subjects will receive follow-up phone 
calls, texts, and/or SendSafe emails at  1 week of enrollment and 1, 2, 3, and 6 months after study enrollment. 
(The choice of calls, texts or emails came from prior subjects who participated in IRB approved study focus 
groups.) The study team has permission from MCIT to send the following text messages (and an emailing 
indicating such approval is part of the submission process): 
1. Please remember to use the app. 
2. Hi, The RELAXaHEAD team is trying to reach you. Please call xxx-yyy-zzz [study phone number]? 
3. You are due for your follow-up call/email. Please be sure to call us at xx-yyy-zzzz or respond to the email. -
The RELAXaHEAD team. 

 
8 
4. Remember-relaxation is beneficial for your health. 
5. The best way to add relaxation into your routine is to pair it with an activity you do each day. Let us know if 
you want to discuss how to improve your adherence with the RELAXaHEAD app. 
6. Research has suggested that the more one is able to practice relaxation, the better one's health. Log into the 
RELAXaHEAD app when able. 
7. 
We will text participants once a week from our NYU MCIT study phone confirming that we have recorded 
that they have spent x amount of time practicing PMR within the application, and asking if they have practiced 
PMR independently without the application that week. 
 
Follow-up will be assured by testing the subject’s phone number in front of the subject and asking for alternative 
contact information. Subjects will also be called/emailed.texted after 3 days of no daily diary entry. If they are 
not reached, an email via HeadacheResearch@nyumc.org will also be sent as a reminder to input the data. 
During the calls, a designated study team member will reiterate the importance of adherence with the app. At 
1,2 and 3 months, subjects will be asked to complete the MSQv2 and the MIDAS via phone or email to assess 
the treatment benefits. A designated study member will call the patient if they do not complete the assessment 
electronically. Throughout the study, subjects will be asked to record electronically any new and/or discontinued 
medications and interactions with the medical community. The study team also wants to collect additional 
patient information such as medications used before and after the research study (especially opioids), 
healthcare utilization, and comorbid diagnoses via i2b2, a member-driven non-profit foundation developing an 
open-source / open-data informatics community. 
In addition, if any subject contacts us and want to withdraw from the study, we will ask them to complete the 
MSQv2 and MIDAS before they withdraw.Subjects who withdrew will be contacted via telephone or email at 
the end of the 6 months study period in order to verify their email address to be used to send the 
reimbursement gift card for their study participation. An IRB approved telephone voicemail and email script 
will be used. An attempt will be made to reach the subject via telephone and a voicemail will be left if 
unanswered. Following this, an email will be sent. 
In addition, we will be conducting focus groups of patients who consented for the study to obtain additional 
feedback regarding the study procedures. Focus groups will range from 3-7 people with a goal of 5 participants 
per group. Participants will receive invitations to participate in the focus groups over telephone or over email. If 
they agree to do so, they will sign an informed consent form at the focus group meeting. Participants will be 
given a $50 dollars for participating in the group. The focus group duration will be one hour. 
Symptoms Diary 
On the smartphone application platform developed by IRODY [end user agreement was already signed as part of 
prior study-see attached] (used by the NYUMC epilepsy group for ongoing IRB approved studies and in another 
IRB approved headache study), subjects will be trained to keep records of headache occurrence, side effects, 
compliance and medicine changes on their mobile device. If a subject fails to consistently record their data, they 
will receive a call from the RV at NYU to ensure compliance with data maintenance. Information prompted by the 
device will include: 
1. 
Headaches (number, intensity, duration, time) 
2. 
Abortive and preventive migraine drug treatment 

 
9 
3. 
Concomitant medications 
4. 
Episodes of non-compliance 
5. 
Changes made to migraine medication treatment plan, if any, and reasons for the change 
6. 
Adverse effects, including severity, seriousness, unexpectedness as part of pharmacovigilance 
7. 
Mood and anxiety and stress levels, sleep quality and duration 
8. 
Healthcare utilization 
The symptoms diary may be accessed via the mobile application only. 
The study team will not share the symptoms diary information with the subject’s treating physician. However, 
subjects can elect to share their data with their treating physician independently. 
The following questionnaires: PROMIS depression and anxiety screens, Insomnia Sleep Index (ISI) and the 
Perceived Stress Scale will be administered via REDCap. 
In addition to the application, REDCap, a HIPAA Compliant research database system will be used. The study 
identifier and the PHI of the subjects will be stored in REDCap. In addition, we will use REDCap to send out the 
MIDAS to the subjects. 
We will use the REDCap randomization feature to randomize our subjects. 
D a t a A n a l y s i s a n d D a t a M o n i t o r i n g Analysis  
Plan 
Table 2 describes the outcome measures that will be used. We considered the feasibility outcome measures 
recommended by Kraemer and colleagues for pilot studies.31 For this study, feasibility will be operationally 
defined as study recruitment, retention, and adherence measures for doing the PMR. Acceptability will be 
operationally defined as attrition, satisfaction, and willingness to participate in a similar intervention in the 
future. Satisfaction questions are as follows: 
Responses will be 0–5 on the Likert Scale:  
Daily Diary Satisfaction Questions 
1. The app was easy to use 
2. The information was easy to understand 
3. The daily diary was relevant to me to help track my headaches 
4. The app kept my interest and attention 
5. I would be happy to use the app again 
PMR Satisfaction Questions 
1. The relaxation kept my interest and attention 
2. The relaxation helped to improve my stress and low mood 
3. The relaxation taught me skills that will help me handle future problems 
4. I would be happy to do the relaxation again 

 
1 0  
O ur pri m ar y o ut c o m e will b e t h e c h a n g e i n t h e M S Q v 2 -a v ali d at e d mi gr ai n e q u alit y of lif e m e a s ur e  
( htt p s:// e pr o vi d e. m a pi-tr u st. or g/i n str u m e nt s/ mi gr ai n e-s p e cifi c -q u alit y -of -lif e-q u e sti o n n air e). W e will al s o u s et h e 
Mi gr ai n e Di s a bilit y A s s e s s m e nt S c al e ( MI D A S), m e a s ur e s di s a bilit y o v er t h e p a st 3 m o nt h s.
3 2 -3 5 MI D A S s c or e s 
h a v e b e e n s h o w n t o h a v e e x c ell e nt t e st -r et e st r eli a bilit y, hi g h i nt er n al c o n si st e n c y, a n d hi g h e xt er n al v ali dit y 
u si n g a v ari et y of m e a s ur e s — i n cl u di n g di ar y-b a s e d m e a s ur e s. 3 2, 3 4 MI D A S s c or e s  ar e al s o p o siti v el y a s s o ci at e d 
wit h p h y si ci a n j u d g e m e nt s a b o ut t h e s e v erit y of h e a d a c h e a n d t h e n e e d f or tr e at m e nt. 3 3 I n t h e M S- mi gr ai n e 
p ati e nt p o p ul ati o n, w e will al s o a s s e s s t h e M O S P ai n Eff e ct s S c al e ( P E S).  
Di s a bilit y i s a c o m m o nl y u s e d o ut c o m e i n mi gr ai n e tri al s e v al u ati n g o ut c o m e s of a c ut e a n d pr e v e nt ati v e 
i nt er v e nti o n s,3 6, 3 7 b e c a u s e it i s e a s y t o u n d er st a n d a n d i s m e a ni n gf ul t o p ati e nt s.  
T A B L E 2 : O U T C O M E M E A S U R E S: D E FI NI TI O N S A N D S C A L E S 
Ai m 1: F E A SI BI LI T Y A N D A C C E P T A BI LI T Y O U T C O M E S  
F e a si bilit y: a) Pr o p orti o n of p ati e nt s w h o e nr oll e d i n t h e st u d y/ w er e r e cr uit e d f or t h e st u d y, b) P er c e nt a g e of p ati e nt s w h o di d P M R  
≥4/ 7 d a y s of t h e w e e k, c) N u m b er of d a y s s p e nt d oi n g P M R ≥5 mi n ut e s/ d a y a s d et er mi n e d wit h t h e b a c k e n d a n al yti c s i n t h e 
R E L A X a H E A D a p p, d) Mi n ut e s/ d a y s p e nt d oi n g P M R, e) R e a s o n s f or n o n -a d h er e n c e  
A c c e pt a bilit y: a) S ati sf a cti o n u si n g Li k ert s c al e q u e sti o n s o n R E L A X a H E A D u s a bilit y, c o nt e nt, a n d f u n cti o n alit y b) Willi n g n e s s t o 
r e p e at a si mil ar tr e at m e nt i nt er v e nti o n i n t h e f ut ur e ( D efi nit el y N o/ Pr o b a bl y N o/ U n s ur e/ Pr o b a bl y Y e s/ D efi nit el y Y e s) c) Attriti o n 
Ai m 2: MI G R AI N E Q U A LI T Y O F LI F E A N D MI G R AI N E DI S A BI LI T Y O U T C O M E S  
Pri m ar y O ut c o m e = F u n cti o n alit y: MI D A S: diff er e n c e b et w e e n s c or e s of MI D A S 
3 2, 3 8 at 3 m o nt h s a n d b a s eli n e. M O S  P ai n 
Eff e ct s S c al e ( P E S).  
P ai n: 5 0 % d e cr e a s e i n fr e q u e n c y a n d/ or i nt e n sit y of H A s ( m e a s ur e d b y el e ctr o ni c H A di ar y d at a). 3 9 Will c o ntr ol f or a d h er e n c e wit h 
P M R. ( Fr e q u e n c y : # of H A d a y s/ 3 0 d a y s st arti n g a n d e n di n g at mi d ni g ht; I nt e n sit y: 0 ( n o H A), 1 ( mil d H A), 2 ( m o d er at e H A), 3 
( s e v er e H A) r e c o m m e n d e d b y I H S.3 9 
A c ut e m e di c ati o n s u s e d*: A s r e c o m m e n d e d b y I H S: # of d a y s/ w e e k tr e at e d wit h m e di c ati o n s, # of dr u g a d mi ni str ati o n s/ w e e k f or 
m e di c ati o n s. M e di c ati o n s i n cl u d e d: N S AI D s, a c et a mi n o p h e n, c aff ei n e, a s piri n, tri pt a n s, b ar bit ur at e s, o pi oi d s, a nti p s y c h oti c s.  
P s y c hi atri c C o m or bi dit y, Str e s s L e v el s, a n d Sl e e p: P R O MI S d e pr e s si o n a n d a n xi et y s cr e e n s, t h e P er c ei v e d Str e s s S c al e, 4 2 -4 4 
a n d Sl e e p D ur ati o n a n d Q u alit y u si n g Li k ert S c al e q u e sti o n s ( H o w w o ul d y o u  r at e t h e q u alit y of y o ur sl e e p/ H o w r e st e d or r efr e s h e d 
di d y o u f e el w h e n y o u w o k e -u p f or t h e d a y). 4 5 
A d v er s e E v e nt s: P M R : P ar a d o xi c al a n xi et y, ti m e b ur d e n/i n c o n v e ni e n c e, a n d a n y ot h er a d v er s e e v e nt s e x p eri e n c e d. R e c or d e d 
i n r e al ti m e i n t h e st u d y di ar y.3 9 A s r e c o m m e n d e d b y t h e I H S: A d v er s e e v e nt s will b e r e c or d e d a s f oll o w s: E v e nt S e v erit y: Mil d, 
M o d er at e, S e v er e; E v e nt S eri o u s n e s s: S eri o u s, N o n -S eri o u s, St art a n d E n d Ti m e. 3 9 
 
Q u alit y C o ntr ol : T h e d e si g n at e d st u d y t e a m m e m b er will d o w nl o a d t h e d at a fr o m t h e Di ar y Cl o u d S er v er. 
Fr o m t hi s d o w nl o a d, st a n d ar d r e p ort s i n cl u di n g mi s si n g d a y s or e ntri e s a s w ell a s i d e ntifi c ati o n of a n y s af et y 
c o n c er n s will b e cr e at e d fr o m t h e d o w nl o a d e d d at a b a s e a n d e x a mi n e d a n d r e vi e w e d b y t h e PI ( Dr. Mi n e n) 
a n d t h e st u d y t e a m  m e m b er s.  
M e a s ur e m e nt s: D a t a S t o r a g e a n d C o n f i d e n t i a l i t y  
All p ati e nt h e alt h i nf or m ati o n will b e e nt er e d i nt o t h e R E D C a p d at a b a s e. E a c h s u bj e ct will b e a s si g n e d a u ni q u e 
al p h a n u m eri c i d e ntifi er. T h e al p h a n u m eri c i d e ntifi er s will b e u nr el at e d t o t h e i d e ntit y of t h e st u d y s u bj e ct s. T h u s, 
w e will u s e R E D C a p t o st or e t h e c o nfi d e nti al li st li n ki n g s u bj e ct s a n d t h eir al p h a n u m eri c i d e ntifi er s. O nl y t h e PI 
a n d st u d y t e a m m e m b er s will h a v e a c c e s s t o t h e li n ki n g d at a b a s e.  
T h e c o n s e nt f or m s (i n cl u di n g t h e a u di o r e c or di n g c o n s e nt f or m s) will b e k e pt i n a s e p ar at e l o c k e d fil e c a bi n et at 
2 2 2 E a st 4 1 st Str e et 1 4t h fl o or . If s o m e o n e w er e t o g ai n ill e g al a c c e s s t o t h e l o c k e d fili n g c a bi n et wit h  st u d y 
d at a, t h e y w o ul d h a v e n o w a y t o li n k t hi s d at a t o  a n y i d e ntif yi n g i nf or m ati o n. T h er e i s n o pr ot e ct e d   h e alt h 
i nf or m ati o n o n t h e r e c or di n g s a s t h e st u d y t e a m m e m b er s will b e i n str u ct e d  t o st art t h e  r e c or di n g s  aft er t h e 
p ati e nt s h a v e b e e n i d e ntifi e d.  
T h e r e s e ar c h t e a m will p erf or m all d at a a n al y s e s. T h e d at a c oll e ct e d a n d st or e d b y I R O D Y i s st or e d i n a m a n n er 
a p pr o v e d b y t h e N Y U M CI T. T h e d at a will t h e n b e tr a n sf err e d b a c k t o t h e PI a n d d at a will b e st or e d el e ctr o ni c all y 
i n a s e c ur e r e s e ar c h d at a b a s e a n d will b e a v ail a bl e f or t h e r e s e ar c h t e a m. 

 
11 
Research subjects will be assured that participation or non-participation in this investigation will not influence in 
any way the patient’s treatment by his or her healthcare providers, and will not influence any future interactions 
he or she may have with NYU Langone. 
The application produced by the company IRODY has been used by other researchers in the department of 
neurology at NYUMC. The symptoms diary on the mobile device used by subjects will be secured to comply 
with data privacy and other regulatory requirements. Data security is maintained by having a secure data 
protocol, which encrypts the information being sent from the mobile device to the cloud server and vice versa. 
The server is protected by a firewall. Daily backups will be performed. The app will not hold any personally 
identifying details and will be linked only to the Subject ID. The app does not collect any personal information 
from the mobile device. As stated above, the RVs and PI will have access to the symptoms diary data, as well 
as all subjects’ names and phone numbers, in order to contact any participants who forget or are unable to enter 
their information in a timely manner. The RVs and PI will access the symptoms diary data only for the purpose 
of ensuring data completion and will not disclose any subjects’ PHI. 
Risk/Benefit Assessment  
R i s k 
Risks from PMR: There is minimal harm in doing PMR therapy. PMR may cause some pain in previously injured 
sites. It may also cause some flooding of memories. If this occurs, subjects will be directed to turn their thoughts 
elsewhere. If this method is ineffective, subjects will be told that they can stop performing the relaxation. 
Potential Breaches of Confidentiality: There is a small risk of breach of confidentiality. Protections against this 
are described. 
P r o t e c t i o n A g a i n s t R i s k s 
As stated above, subjects will be warned of the side effects. 
P o t e n t i a l B e n e f i t s t o t h e S u b j e c t s 
Subjects may benefit by having decreased migraine disability and by having their migraine pain decrease in 
severity and/or frequency with the PMR. 
Investigator’s Qualifications & Experience 
Please see attached. 
Subject Identification, Recruitment andConsent/Assent 
M e t h o d o f S u b j e c t I d e n t i f i c a t i o n a n d R e c r u i t m e n t 
Virtual enrollment Phase 1: 
 
Recruitment will be done via both direct and indirect contact.  
 
Direct Contact: Neurologists may discuss the study with their patient/prospective subject (in person/via 
telemedicine or by telephone) and provide the study physicians contact information, to interested individuals. 
They may also obtain the patient's permission to be contacted by study staff. Any contact between study staff 
will take place with NYU HIPAA compliant email or telephone. Screening procedures have been identified 
earlier in the protocol. 
Physicians will not be contacted if their patients choose to participate because a) they will all have been 
informed about the study before the study begins and b)it is a minimal risk study which should not interfere with 
the treatment plan. 

 
12 
Indirect Contact: Through the Epic research team, we will generate a list of people who were seen with 
headache or migraine in the past 6 months in the practices named above (Neurology, Primary Care and Urgent 
care) who are between ages 18-80 and who have not opted out of being conducted for research at NYU.18–80 
years; Study team members will then pre-screen those to determine whether they might meet migraine criteria 
based on the International Classification of Headache Disorders (ICHD) criteria; Migraine Disability Assessment 
(MIDAS) score >5. 4+ headache days a month In addition, the following PHI will also be captured in the EPIC 
data pull: subject name, date of birth, MRN, telephone number, email address, medical records such as 
admission/discharge dates. 
The following team members will have access to the EPIC search results: Principal investigator, biostatistician, 
research volunteers, research coordinators, and data analysts. The study team will search EPIC daily over the 
course of the study (12 months). As discussed above, the research team (pain and volunteers) will undergo 
rigorous training in study procedures. 
For focus group: study team members will use the focus group recruitment announcement email or telephone 
script to find out if enrolled subjects would be willing to participate in a focus group on what they thought of the 
study. 
As stated above, once contact is made, approved recruitment language will be used to communicate the reason 
they are being contacted and subjects will be asked if they are interested in participating in this specific study 
via telephone or email. Should the potential subjects agree, the study team will provide the subjects with 
information regarding the next steps for participation. Any contact between study staff and potential participants 
will take place with NYU HIPAA compliant email, HeadacheResearch@nyumc.org or through REDCap. Any 
recruitment information sent by email will utilize Send Safe email. 
If a subject requests information regarding opting out of further recruitment for all research, subjects will be 
directed to contact study coordinator or have subjects contact research-contact-optout@nyumc.org or 1-855- 
777-7858. 
Initial Screening Questions for Chronic Post-traumatic headache: 
When did  you  have  your   injury that   led   to   concussion symptoms? Did you develop headaches  
afterwards from the injury? If so, when did you first develop the headaches? 
(Eligible would be 3-12 months post initial injury) 
On a scale of 0-10, what is your average headache intensity? Maximum headache intensity?  
Do you own a smartphone? Yes/no 
Would you be interested in doing daily exercises to treat your headaches? Yes/no 
If they meet criteria, when they come for the NYU Concussion Center appointment, they will be scheduled for a 
session with the RA to discuss the study, obtain informed consent in interested subjects, complete the REDCap 
survey, and download the app. 
P r o c e s s o f C o n s e n t 
Research volunteers or physicians who are study members will obtain consent. As indicated above, research 
volunteers will be trained during an intense one week training on study procedures including an emphasis on 
how to consent the participants. This is a no risk/very low risk study unlike other interventional studies. Thus, it 
is appropriate for trained research volunteers to consent these participants just as they would be able to do so 
for survey type studies. They will be carefully observed during the initial consent process to ensure that they 

 
13 
are doing it correctly. They will explain the rationale for the study (see above) and review the form with potential 
subjects. We will file an IRB addendum later on to add them to the protocol. 
For focus group: subjects will sign an informed consent form in-person at the focus group meeting. 
S u b j e c t C a p a c i t y 
Only subjects with capacity will be asked to participate in the study. 
S u b j e c t / R e p r e s e n t a t i v e C o m p r e h e n s i o n 
Subjects will be asked to explain that they understand that they may or may not be offered this additional 
intervention and that the determination of whether they are offered it is random. 
Subjects will be asked to explain that they understand that they will be asked to do a daily relaxation exercise 
and that they will be asked to record their headache characteristics, mood, anxiety and stress levels on the 
smartphone app as well as the number of hours that they slept/sleep quality. 
D e b r i e f i n g P r o c e d u r e s  
N / A 
Data Safety Monitoring Plan 
The PI will be responsible for data safety monitoring. This is a minimal risk device. Minimal to no risk is expected 
for participants in the study. Only the PI, RVs and any future co-investigators will have access to the data. Co-Is 
would be added to the IRB at a later date. No personal/identifying information will be kept on an insecure site. 
No personal or identifiable information will be stored within the app. The PHI will be stored in REDCap. We will 
report all unanticipated events within a 24- to 48-hour time window or as soon as possible. There are no 
predetermined criteria for action. 
C o n s e n t F o r m s 
A consent form for each subject will be obtained. Please see attached. 
D o c u m e n t a t i o n o f C o n s e n t 
The documentation will be kept in a locked storage unit in Dr. Minen’s office on the  14th floor of the Department 
of Neurology, 222 East 41st street, New York, NY 10017. 
P a y m e n t f o r P a r t i c i p a t i o n 
There is payment for participation for all subjects. They will receive $25 for the initial survey and then $1/day for 
up to 60 days (the initial 60 day period) for data entered. If they complete 80% or more of the initial 60 day 
period, then the daily amount paid will be doubled. In addition, they will receive $15 for the one month and two 
month followup email or call and $25 for the 3 month and 6 month followup email or phone assessments. The 
maximum amount they can be paid is $225. The subject reimbursement amount is commensurate with other 
headache related smartphone application studies throughout the country. 
July 2020: Phase 1 subjects: The subjects will receive $25 for the initial survey and then $1/day for up to 90 
days if they complete at least 80% of the days data entry. In addition, they will receive $15 for the one month 
and two month followup email or call and $25 for the 3 month and 6 month followup email or phone 
assessments. The maximum amount they can be paid is $195. They will be paid at the end of 6 month study 
period. 
Cost to Subjects: 
Subjects can connect to wifi if they do not want to incur data usage costs. 
Clinical trial registration will take place after IRB approval has been obtained.  

 
14 
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