Guest: Dr. Deena Kuruvilla

View the recording from our Migraine Clinician Masterclass, developed in partnership with IVPN Neuropsychiatry. In this webinar, we hear from Dr. Deena Kuruvilla, who talks about Understanding Patient-Reported Outcome Measures (PROMs) for Headache Trials and Clinical Practice. Please note that this video is intended for healthcare providers.

TRANSCRIPT

Deena Kuruvilla, MD, FAHS: Thank you so much for having me here with you today. It’s such a great opportunity to meet so many people from around the world today and to talk a little bit about headache disorders, migraine, and also talk about some patient-reported outcome measures today. I’m Deena Kuruvilla. Thank you so much for the introduction. 

I know that sometimes after a presentation or beyond a presentation, questions come up or commentary about the presentation. I’ve included my email on the first slide and the last slide in case anybody wants to discuss the presentation further.

So here are some of my disclosures, some of which may be relevant to today’s conversation. 

So today’s learning objectives include a couple of different things. I wanted to start off the presentation by introducing headache disorders and migraine specifically, talking a little bit about how we diagnose these conditions and use those diagnoses in our clinical practice.

The second thing we’ll do is we’ll review the different criteria that’s necessary to provide the patient with an accurate diagnosis and the right treatment options. 

And then we’ll also highlight what are really the meaningful outcome measures that we have for migraine research. You know, the landscape of migraine research has changed so much over the past 20 years. And over time, the different outcomes that we use in each clinical trial have been so different, and there’s been such a large variety. So we’ll discuss a little bit of that variety today. 

We’ll also look at, in addition to research, we’ll look at some clinical outcomes that may be relevant to you as you’re seeing these patients in your clinical practice, different markers that you may be able to follow so that you can accurately diagnose the patient and also treat the patient effectively.

And we’ll also end the talk today with a little bit about patient preferences. What do patients want out of our encounters, and what do they want out of their interaction when they talk about their headache disorder with their provider? 

So to start off today, you know, the most common headache disorder that I definitely see in my clinic, and you know, certainly the most common headache disorder here in the United States is migraine. I would even take it one step further to say that I personally think that a lot of the people that we diagnose with other conditions, such as tension-type headache just as an example, or the really common one that people kind of diagnose themselves with sinus headache, I think these people truly probably have migraine. And I really do think it’s the most common headache disorder, and this is by far 90 to 95% of the headache disorders that I see in my clinic. 

A lot of the data that we have in the literature about patient-reported outcomes specifically refers to migraine. So that’s another reason why we’ll focus a lot on migraine today. We don’t have as much data about patient-reported outcomes in other headache disorders, such as cluster headache, tension-type headache, many of the trigeminal autonomic cephalalgias, or trigeminal neuralgia, for example. So that’s a big part of why we’ll focus on migraine today. And hopefully, as the research about outcomes evolves over time related to migraine, we’ll have more patient-reported outcomes for other conditions, facial pain syndromes, and other headache disorders.

But to start off here, we know that migraine is an inherited disorder that’s characterized by neurological, it’s a neurological disease that has a sensory component, autonomic component in many cases, a vestibular component in some cases, cognitive changes, and gastrointestinal symptoms. I tell a lot of my patients that the genetic component really trumps everything when it comes to a migraine diagnosis and the likelihood of somebody having migraine, in addition to environmental factors and lifestyle factors. But really, the genetics trumps a lot when it comes to migraine disease.

We know that in 2016, the Global Burden of Disease Analysis reported that migraine is the second leading cause of years lived with disability. And so this is pretty much what I see in patients who come through my office also. This is such a burdensome disease, and it’s a disease that carries so much disability when it comes to disrupting one’s personal life, professional life, and interpersonal relationships with other people.

We know there’s around 1 billion people with migraine worldwide. 1 in 5 women may experience migraine, and one in 16 men, and one in 11 children experience migraine. And so being that this is a disease that affects so many people and such a variety of people regardless of age, race, whatever it may be, we really need to come up with better outcome measures as we move forward in scientific research.

So women are, by far, most commonly affected by migraine, and this is just a chart breakdown of the ages and prevalence that we see people affected. Certainly, I see people of all of these ages, but certainly we see that the biggest peaks in migraine prevalence are women of childbearing age and women who may be going through the perimenopausal or postmenopausal period as estrogen fluctuation is going on. 

So it’s really interesting. I think that research may also evolve moving forward, specifically looking at outcomes in women who are affected in the perimenopausal period specifically and during the childbearing years. Today’s outcome measures that we’re going to be talking about are very nonspecific for the general population, regardless of race/gender. So it’d be nice to have more outcome measures moving forward that are really targeted to women in these age groups.

This is kind of the guide that I use in my clinic when I’m diagnosing people with headache disorders, and this is the guide that I often show to students and fellows and residents just to confirm that we’ve reached the right diagnosis when it comes to a specific headache condition. The International Classification of Headache Disorders was last revised, in 2013, and basically has the definitions for a variety of headache disorders and also special highlighted excerpts for specific treatments that may be very specific to a headache condition. So I find this very helpful.

The International Classification of Headache Disorders is available online in a PDF format and also in a non-PDF format just by googling International Classification of Headache Disorders. I also find that this is very helpful when talking to my patients about a diagnosis. Sometimes patients don’t believe when I discuss a migraine diagnosis with them, and so sometimes I’ll open this up and show them, you know, this is A, B, C, D, E, F of what you may have, and it makes the patient really trust the diagnosis and the process much more.

And so I just pulled out a couple of different definitions from the International Classification of Headache Disorders here. The first one here is migraine without aura, and we know that this is a recurrent headache disorder that usually lasts from 4 to 72 hours, and in most people, the pain is unilateral, side-switching, maybe of pulsating quality, and these are the specific criteria. And also that the pain should be moderate or severe in intensity, and it can have worsening on exertion and be associated with nausea and/or vomiting or photophobia and phonophobia. 

And so this is the typical criteria that I use to diagnose patients who have migraine without aura, as long as I’ve ruled out other secondary causes for headache. When I’m seeing a headache patient for the first time, I do make sure that I rule out other secondary causes for headache before I land on one of these primary headache diagnoses. 

And these definitions for migraine that I’m reviewing right now are directly from the International Classification of Headache Disorders, and these are the definitions that are used in migraine clinical trials, in our treatment trials. The standardization of these definitions have given us such a higher quality of clinical trial participants, because we make sure in many of the clinical trials now that participants meet these exact criteria before they’re enrolled, and in most cases, in larger randomized placebo-controlled trials, patients have to go through anywhere from a six- to eight-week screening period and document diary data that specifically fulfill this International Classification of Headache Disorders criteria.

And so not only does it have use in clinical practice, it also has a lot of use in the standardization of patients that we’re including in these migraine treatment trials. It’s such an important, this is such an important document. 

And I also included a definition here for chronic migraine, because these patients can be more difficult to diagnose, and in many cases, when we ask a patient in clinical practice, how many headache days are you having a month, they often only report the most severe days.

So now I’ve kind of had to change my questioning in clinical practice and also in research, and I’ve had to ask patients, how many days in a month do you have no discomfort in your head or your neck? And when I ask that question a little bit differently, they include those milder pain days in addition to those moderate and severe pain days. So I’m able to capture a more realistic view of what the total number of headache days is. 

So for people with chronic migraine, people with chronic migraine make up around 2 to 4 million people in the United States. This is a headache that’s occurring on 15 or more days a month for more than three months, and these headaches over this period should be of a migrainous quality on at least eight days per month.

And so this is a very common thing that I see in clinical practice. You know, certainly as a headache specialist, I do tend to see more of the more intractable patients, but I really do think chronic migraine is much more prevalent than we see in the epidemiological studies currently. 

Right now, the balance that we see in the US is that 40 million people in the US have episodic migraine, they have less than 15 headache days a month, and 2 to 4 million people in the US have chronic migraine. But I do think that number for chronic migraine is actually higher, because we may be asking the question incorrectly to patients when we’re enrolling them in studies or seeing them in our clinics. 

And I’ve included a definition for medication overuse headache here, because many of the clinical trials that are specifically looking at migraine therapeutics have to include this definition and screen for medication overuse headache in order to have a more pure participant pool in the study. We often do not want to include participants in clinical trials who have medication overuse headache, because then that can confound our results ultimately in the final sample.

And for our medication overuse criteria, these are people who have regular overuse for greater than three months of one or more drugs that can be taken for acute or symptomatic treatment of headache. And all of these people should be reporting 15 or more headache days a month. So, in all of the people that we see for chronic migraine, they should be regularly screened for medication overuse headache also.

And this is such an important population to exclude when we’re looking at clinical trials. And in clinical practice, this is a really important population to identify to be able to cut out acute treatments and optimize preventive therapies, because it’s very manageable and treatable. 

So, here are some of the treatment goals that we really want out of not only our clinical practice, but also within migraine clinical trials.

So, for treatment goals for preventive treatments, we’re really looking to cut down on the frequency, severity, and duration of attacks and improve response to acute treatment. One of the biggest things for patient preference is to reduce the overall disability. And so, many of the clinical trial outcomes we’ll see today are looking to measure these specific things. And this is what we want to monitor in our clinical practices as well. 

As far as acute migraine treatments go, our aim is really to resolve migraine pain and the associated symptoms. So, our nausea, vomiting, photophobia, and phonophobia when an attack occurs, and try to get the patients back to a normal level of functioning as soon as possible.

So, why are these definitions actually important to us? Why do these make a big difference? You know, I would say that having a standardized system to diagnosing patients improves education among our medical colleagues. You know, because one common thing we see is misdiagnosis. And so, having a fixed definition for each headache disorder really increases the chance of reaching an accurate diagnosis. And having an accurate definition really helps us to specify the treatments that work for that particular condition. 

Standardizing outcomes, in particular, is important to clinical trials so that we can compare apples to apples when we’re looking at preventive therapies and seeing is one preventive therapy, is their benchmark of overall reduction in headache days the same as its competitor. And so, standardizing the outcomes and those benchmarks really help us to compare apples to apples rather than oranges to oranges.

And I think it’s very important to differentiate the outcomes that we have for preventive treatment compared to acute treatment, and even nonmedication approaches, which are not commonly talked about, such as devices, nutraceuticals, and behavioral approaches, such as biofeedback and relaxation and cognitive behavioral therapy. I think that standardizing the outcomes across the board, not just with pharmaceuticals, is of utmost importance. Because if we expect our nonmedication options to work similarly to mainstream medicine, then we have to be looking at similar outcomes in clinical trials.

One example of non-medication options using similar outcomes are the devices, the migraine devices. We have about five FDA-cleared migraine devices for acute treatment and preventive treatment, either/or in some cases. And in each of the clinical trials, the devices were compared to sham devices, and they did use the same endpoints in many of the migraine medication trials that we used. So that’s really nice that we’re starting to see more of that standardization with outcomes in clinical trials. 

And with research considerations, what do we need to know about primary outcomes? That’s the next thing. 

So the standardization of outcomes has changed dramatically in the last 10 years or so pretty significantly. And one of the interesting developments that has come up in 2015 is the development of BEST. Now, this is a partnership between the National Institute of Health, the NIH, and the FDA to start to standardize definitions for specific disease states and also to standardize biomarkers across different disease states.

So this is a really nice book that’s periodically updated that really looks at specific definitions for different disease states that should be used in research considerations for the most part. And so really using this resource has been helpful for putting together different clinical trials for different disease states and the treatments to go with those. And so this is a really nice reference to consider if you’re going to be putting together a research trial for a specific disease state.

So that brings us to the prevention of migraine. During today’s talk, we’ll separate prevention and acute treatment because they’re treated completely differently in migraine with different goals, different outcome measures, and they’re studied completely differently. And the treatments, of course, completely differ as well.

I thought that we could start off here by reviewing this consensus statement that came from the American Headache Society actually at the peak of COVID. It was in 2020, I believe, this consensus statement came out from the American Headache Society about how to integrate newer migraine treatments into clinical practice. And this was by Dr. Ailani and colleagues. And this is the article that I often reference when I’m initiating preventive therapies for my patients or layering different preventive therapies. 

This table summarizes the medications that have proven efficacy for the prevention of migraine. There is one missing here that I can identify, which is atogepant, which received FDA approval for the prevention of migraine after this guideline came out. And I will say the other thing that’s not added here is rimegepant receiving FDA approval for the prevention of migraine. Both of these medications are oral CGRP receptor antagonists that are a tablet that are used for the prevention of migraine. Rimegepant is taken every other day, and atogepant is taken daily. So those are the only two that are missing here. 

Apart from those two, we have our standard blood pressure medications, seizure medications with divalproex and topiramate. And we have our antidepressants, which most commonly used are tricyclic antidepressants, and our serotonin-norepinephrine reuptake inhibitors. 

We have our injectable CGRP monoclonal antibodies. And our infusion, the three are autoinjectors – erenumab, fremanezumab, and galcanezumab. And eptinezumab is our infusion that’s administered quarterly. And our standard onabotulinum toxin, which has been FDA approved for the prevention of chronic migraine since 2010. 

The other thing, we do differentiate here preventive treatments between chronic migraine and episodic migraine. And the last thing I’ll highlight here is that onabotulinum toxin A and atogepant, atogepant was recently FDA approved specifically for the prevention of chronic migraine. So, you know, identifying those patients that may benefit from treatment may be very helpful. 

And so these are just some of the factors that help with the optimal selection of preventive treatment. You know, in my practice, I try to gauge what would be most tolerable for the patient based on other treatments they may be taking, their lifestyle, and really what the patient preference is in many cases. You know, that’s a huge factor for deciding on preventive treatment. 

And then, of course, in the US, we’re kind of have to look at the cost and insurance coverage of each individual treatment when making these considerations too, in addition to the patient’s individual medical comorbidities. 

And so let’s talk a little bit about clinical outcomes. There is not too much out there in the literature about patient-reported outcomes for migraine, but there are a couple of articles that are systematic reviews that start to describe outcomes and endpoints for preventive migraine therapies. 

This first one that was released, it actually just came out in 2021, specifically looked at endpoints for preventive treatment. So, in this particular systematic review, they looked at around 268 publications and looked at the various outcomes that were looked at for preventive therapies.

And I’ll just highlight here that the most common ones that we tend to see currently when we’re looking at migraine treatment trials is the change from baseline in monthly migraine days. In many of the studies that have been done recently, especially for CGRP monoclonal antibodies and with the gepants, namely rimegepant and atogepant, we looked at the reduction in monthly migraine days over a 12-week period. And in these trials, the baseline number of migraine days, we really wanted to see how much of a reduction in baseline over each individual month in that 12-week block and also overall those 12 weeks, what the average reduction in those monthly migraine days was.

In many of the recent studies, we also looked at a greater than or equal to 50% reduction in monthly migraine frequency, a greater than or equal to 75% reduction in monthly migraine frequency, and an average of a 100% reduction in monthly migraine frequency. And so, I think I can safely say that for the past five years, most of the studies have included these exact outcomes very uniformly. It’s been very good that a lot of the newer treatments have used this fixed outcome in their studies specifically.

The other thing that I found really interesting looking at this study is that not all the studies looked at migraine specifically in the outcome measure, but they also looked at just generally a headache-focused outcome. And so, I thought that was very interesting. You know, if we’re studying a specific treatment for migraine specifically, it’s interesting to make sure to pin down that specific definition and diagnosis during the screening period.

And a little bit more about this systematic review, we found that more specifically around 69% of the publications looked at a greater than or equal to one migraine-specific outcome, and around 40% examined a greater than or equal to one headache-specific outcome. About 50% to 51% of studies looked at acute or rescue medication use outcomes. Did these participants, did they cut down on their overall use of acute medication with the preventive therapy? And we looked at 40% of the studies looked at patient-reported outcome measures, such as our disability assessments. And we’re going to talk a little bit about those different surveys that are used in preventive migraine trials specifically. 

But the big thing to really draw from this systematic review of 268 articles is that the outcomes varied very significantly. 

So I promised you a couple of different assessments. So for patient-reported outcomes in preventive migraine trials, patients are typically given a disability assessment during the study. And over the course of most of these studies, which are around 12 weeks, we give them one or more, one or two or more disability assessments to see if they’re able to improve their disability with the preventive therapies. 

Classically, we use the migraine disability assessment test, which is the MIDAS assessment. And these are some of the specific questions that are asked to patients. And we’re able to tally a point system here to get their score. And one of the questions is, just as an example, how many days in the last three months did you miss work or school because of your headaches? Or for example, on how many days in the last three months did you have a headache? 

And so based on the patient’s number, we can tell here which grade they have, one, two, three, or four. Do they have little or no disability? Do they have zero to five points? And as we go up here, if somebody has more than 21 points, they have severe disability. 

MIDAS is, I would have to say, one of the more common disability assessments that’s used in clinical practice. You know, when I ask people at the meetings which disability assessment they use in headache clinics, the MIDAS is probably the more user-friendly survey that’s used for patients to monitor their disability.

We also have the Headache Impact Test, which is the HIT-6. And this is just another six-question assessment that’s used. For example, when you have headaches, how often is the pain severe? And in this questionnaire, the more points you have, the higher your disability is as well. So with the MIDAS and the HIT-6 assessments, the larger number of points you have, the higher disability you have. So these are definitely two assessments used in clinical practice. 

More recently, in research studies, the Migraine-Specific Quality-of-Life Questionnaire is the more common assessment, validated assessment that’s been used. Specifically, the Migraine-Specific Quality-of-Life Questionnaire goes from zero to 100. And basically, the higher number of points you have, the less disabled you are. A zero basically means that you’re completely non-functional, and 100 means that you’re fully functional. So opposite from the MIDAS and the HIT-6 point-wise. 

But in the more recent calcitonin gene-related peptide studies, namely the monoclonal antibodies, the Migraine-Specific Quality-of-Life Questionnaire was used to see if patients gained points with their treatment over that 12-week period in the clinical trial. And so the more points that patients were able to gain, the more functionality they gained.

And so these are validated questionnaires classically in research and certainly have different roles in clinical practice and different roles in our randomized placebo-controlled trials. 

So that brings us to acute treatments here. The same author, this is the same article that I showed you earlier. This is the consensus statement that was released. They included preventive therapies in the article and acute therapies, and they briefly touched on devices that are FDA-cleared for migraine, and they also touched briefly on behavioral approaches and other non-medication approaches. 

So here are the acute treatments that have shown evidence of efficacy in migraine. We know that the treatments with established efficacy are our triptans. We have seven of them available in the US of varying half-lives. We have two that are of a longer half-life, naratriptan and frovatriptan, and the other five are which have a shorter half-life. 

We have our ergotamine derivatives, our gepants. From an acute treatment standpoint, the two that are FDA-approved are rimegepant and ubrogepant. We have lasmiditan, which is our first 5-HT1F serotonin agonist acute treatment. And then we have our classic NSAIDs, which are regularly used as well. 

And so this is a different systematic review that really looked at the outcomes and endpoints in acute migraine clinical trials. And many of the endpoints that we’re going to discuss here also have become more uniform since 2018, since the FDA has changed the rules a little bit with measuring endpoints in acute migraine treatment trials, and we’ll talk about those.

And so prior to 2018, the big primary outcome from acute migraine treatment trials was pain relief, and so we’ll see here that the majority of the, they included about 451 studies in this systematic review. The vast majority, you know, certainly looked at pain relief. As of 2018, the primary outcome that’s required for migraine acute treatment trials is pain freedom at the 2-hour mark. And so we see that number coming up here as kind of the second outcome that’s more commonly measured now.

There’s also rescue medication use. After the initial acute medication that’s been studied has been used, what other rescue medications were needed within that 24-hour mark after the study drug was used? We also look quite commonly now at secondary endpoints that include headache recurrence within 24 hours and 48 hours, and we also look at the absence of associated migraine symptoms very commonly as a secondary endpoint now. The absence of the most bothersome symptom, for example, such as nausea, vomiting, photophobia, and phonophobia. Classically, we looked at all of the associated symptoms, but more commonly nowadays, we’re looking at the most bothersome symptom. And of course, we’re looking at disability and impairment in this population as well.

In acute treatment trials, the big question is always how quickly were patients able to return to their regular functioning with no disability? Is it the 2-hour mark, the 4-hour mark, the 8-hour mark, the 24-hour mark? Those hourly marks to return to functioning are the biggest benchmark that we’ve used more recently in acute migraine treatment trials. 

We have our acute treatment benchmarks here. Of the 450 or so articles that were included in the systematic review, 72% looked at pain relief, 65% looked at that pain freedom at 2 hours.

Freedom or relief from migraine-associated symptoms was around 66%. Use of acute rescue medications was around 65%, and disability was measured in around 41%. But I will say, also in this study, we saw a variety of endpoints, and not everybody had the same secondary endpoints in particular. Even though they had, for example, pain freedom at 2 hours as the primary endpoint, the secondary endpoint certainly varied from study to study for these acute migraine treatment trials. 

Here’s an example of one of the validated questionnaires that is specifically for acute treatment of migraine. This is called the Migraine Treatment Optimization Questionnaire. This is a shortened version with just about five questions that can be used to gauge if an acute treatment is working optimally in a clinical trial or even in a clinical practice. Are you able to return to your activities quickly? Can you count on your migraine medication to relieve your pain within 2 hours for most attacks? Is it well tolerated? These are some of the common questions that I ask in clinical practice as well. This is a validated questionnaire.

What about our clinical considerations? This was an interesting study that was done in Europe with over 1,000 patients surveyed. This was a retrospective chart review. They looked at people who basically got these varied diagnoses of general headache in 64%, migraine in 28%, cervical pain in 4%, sinusitis in 1%.

They found that the vast majority of these people actually had migraine despite getting all of these other diagnoses. We found that only 35% of specialists, of which 51% were neurologists, actually diagnosed patients correctly with migraine. Coming to an accurate diagnosis and having standardized definitions is so important so that we’re diagnosing and treating correctly.

What about patient preference? This is a really interesting qualitative study that came out last year that looked at what the patient wants. With these patients, we have about 459 patients that were looked at in this study and 21 publications. 

The eight themes that patients want out of an encounter with their provider for migraine is shared decision-making, a tailored approach. They want to be able to trust their healthcare professional. They want to hear about a diversity of treatment options that are non-medication and medication. They want some holistic approaches in addition to mainstream medications. They want to be able to understand complex treatments. They don’t want to be undermined or the patriarchal approach to treating patients is not preferred by patients. And they want to have mutual respect between the patient and the provider.

While a lot of these seem very obvious, I think it’s really hard in talking to patients for them to get all of these eight things out of an encounter. It’s very difficult to make a partnership that works, a professional and respectful partnership where the patient feels comfortable asking questions and sharing ideas effectively. 

This is really interesting. In this study, they actually preferred non-pharmacological approaches. They wanted their treatments to have high effectiveness, work fast, have a long-lasting effect, be cost-efficient, be easily accessible, and they wanted to be able to give themselves the treatment so that they can really have autonomy over those treatments. They had a mixed preference for preventive treatments and as-needed treatments.

As far as patient-reported outcomes goes in this study, the patient goals for outcomes were improving function, avoiding side effects, not getting addicted to their treatments, not having recurrence of the pain, and avoiding their migraine-associated symptoms, so that nausea, vomiting, sensitivity to light and sensitivity to sound. 

In summary, we looked at a lot of different definitions today. We looked at patient-reported outcomes from three different perspectives. We looked at this data from a clinical perspective for when we encounter patients in our practices. We looked at it from a research, clinical trial perspective. And we looked at it from a patient perspective.

I hope that this was helpful. I would love to take any questions that you have for me now.

*The contents of this video are intended for general informational purposes only and does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. AMD and the speaker do not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.