PREDIMIGRAINE: Precision medicine to prevent migraine chronicity through the prediction of pain crises and response to treatment with anti-CGRP antibodies using multi-omics strategies

PMP22/00158
Year: 2022
Autonomous Communities: MADRID

Summary

Chronic migraine (CM) has a prevalence of 1-2% in the general population, even higher in women and those of working age. CM is usually the result of a transformation in an episodic way, but so far the possibility of reversing the process is low, without individual data from the different disciplines having been shown to be good predictors of this chronification-dechronification process.

The main objective of this project is to establish a personalized and targeted therapeutic strategy that reduces the socioeconomic impact of migraine through predictive tools that allow a reduction in its chronification. To this end, two fundamental lines of action are proposed:

  1. Prediction of the pain phase in migraine attacks in patients with high-frequency episodic migraine (PREDICRISIS). Two of the factors of chronification in migraine are the excessive or insufficient use of analgesic medication. In this way, early and targeted treatment in migraine attacks would reduce chronification. This would be achieved through a wearable ambulatory monitoring device and a mobile application with prospective real-time records that allow the evaluation of the alteration in biometric variables in the hours or days prior to pain, and the characteristics of the pain, respectively.
  2. Prediction of initial and sustained response to calcitonin gene-related peptide (CGRP) monoclonal antibodies in patients with high-frequency episodic migraine and CM (PREDICTGRP), through molecular (CGRP, amylin), transcriptomic (microRNA), genetic (DNA methylation), and neuroimaging biomarkers. Anti-CGRP antibodies are effective treatments to reduce migraine frequency, but not all migraine patients respond to these expensive treatments, and in those who do, there may be a worsening after discontinuation of the drug. Thus, the combination of the different multi-omics markers using machine learning is shown to be an interesting tool for predicting response or non-response/irreversibility.

With all this, the aim is to achieve a reduction in the impact of the disease on the patient’s quality of life and its costs, both direct (medical visits, complementary studies, hospitalization, futile treatments) and indirect (high rate of presenteeism and absenteeism) estimated at two billion euros per year for migraine in our country.

Coordinator and Institution

Principal Investigator
Ana Gago Veiga
Institution
Objectives

The main objective of the project is to establish a personalized and targeted therapeutic strategy that reduces the impact of migraine through a reduction in its chronification.

To this end, two specific objectives are proposed:

Predict migraine attacks. Early diagnosis and treatment of migraine attacks in patients with high-frequency episodic migraine. This would be achieved through a wearable device and a mobile application in real time with monitoring of biometric variables and clinical aspects of pain crises (triggers, prodromal symptoms, pain intensity and other characteristics).

 

  • To demonstrate that it is possible to predict the onset of pain in a migraine attack, through ambulatory and non-invasive monitoring of physiological variables (heart rate, O2 saturation and temperature) using a wearable device.
  • To implement a prediction algorithm based on knowledge and supervised learning through outpatient and non-invasive monitoring of biometric and biophysical variables that allows real-time prediction of the symptomatic phase of the migraine attack.
  • To measure the effectiveness of the prediction model both at the individual level and in large groups of the patient, calculated as the percentage of migraines satisfactorily predicted in a given patient out of the total number of migraines presented.

 

To predict response to initial and sustained treatment to anti-CGRP monoclonal antibodies in patients with high-frequency episodic migraine and chronic migraine through machine-learning tools.

 

  • To validate possible transcriptomic, genetic, molecular and/or radiological characteristics that allow differentiating between patients with high-frequency episodic migraine and chronic migraine in a multicenter cohort at the national level.
  • Establish clinical/demographic/transcriptomic/genetic/molecular and/or radiological characteristics that predict a positive initial response to monoclonal antibodies (biomarkers of therapeutic response).
  • To quantify the proportion of patients who have a sustained response after discontinuation of the anti-CGRP antibody.
  • To determine the time to relapse after discontinuation of the antiCGRP monoclonal antibody in those patients who, having presented a positive initial response, discontinue it.
  • To characterize whether the non-maintained pharmacological response is related to the variables previously characterized as predictors of chronicity.
  • To analyze factors of sustained response at the sociodemographic, clinical, transcriptomic, genetic, molecular and/or radiological levels after the discontinuation of anti-CGRP drugs.
Impact

Migraine is a disabling neurological disease, with a high impact on health systems as it represents a high economic and social burden. In Spain, it affects more than 5 million people. More than 50% of migraine patients have severe or very severe disability, and in patients with chronic migraine the rates of very severe disability reach almost 70%. The group with the greatest disability is 16-47 years old. Migraine is also a disease with a high functional and emotional impact, in which more than 80% of patients have missed social and/or family events due to the disease, even greater in the subgroup of patients with at least two therapeutic failures. In addition, migraine has a very significant effect on presenteeism and absenteeism from work, with a decrease in work productivity from 4 migraine days per month, so it can occur in a large percentage of patients with CM.

Headache accounts for 1 in 5 consultations to a Neurology service, which has been estimated at about 14,000 new consultations per month in Spain. Specifically, migraine consultations account for more than 50% of the first consultations in a Neurology service and more than 80% of referrals to Headache Units are due to cases of chronic or frequent migraine.

The burden of a disease is estimated in disability-adjusted life years (DALYs), which are measured as the sum of years of life lost to premature death (YLLs) and years lived with disability (YLDs). Thus, in migraine, DALYs are equal to YLDs. In 2016, a migraine burden in Spain was estimated at 405,466 YLDs, which accounted for 5.6% of all YLDs (6.8% in women and 4.8% in men). In women between the ages of 15-49, migraine caused 20.3 million YLDs. In the case of ME, the average total economic cost per year is €5,041 per patient, and in CM this cost rises to €12,922 per patient, of which 93% would correspond to indirect costs (2/3 due to reduced productivity).

The treatment of migraine must be personalized and, in many cases, it can and should evolve over time. More than 40% of patients with migraine are undiagnosed, which has a direct impact on the risk of chronification due to misuse of medication. It has been estimated that 50% of patients self-medicate with over-the-counter painkillers and that only 17% use correct medication for the treatment of migraine attacks.

Acute treatment is necessary in all patients with migraine, and should be adapted to the characteristics of the patient, their seizures and degree of disability. The goals of acute treatment are: rapid and persistent relief of pain and associated symptoms; prevent their reappearance; recover functionality; and to optimize patient self-care and reduce the use of health resources (emergency room visits and hospital admissions). Suboptimal acute treatment can lead to increased migraine-related disability and disease progression. The way to assess the effectiveness of the treatment is usually through the interview in the consultation with a calendar. The use of online calendars has proven to be a very useful tool insofar as they facilitate daily access, are available at the time of consultation and can also offer evolutions, summaries and/or statistics.

For some patients, preventive treatment of migraine can reduce the frequency and severity of attacks. However, preventive treatment for migraine is underused: only 1 in 3 candidate migraine patients receive it. Current oral preventive treatments are associated with poor patient adherence and high rates of treatment change and discontinuation. Among the most common causes of discontinuation are loss of efficacy, adverse effects and lack of tolerability, which represents higher direct costs associated with the use of health resources.

All this reflects that migraine has a direct and indirect effect on the lives of patients who suffer from it, who suffer significant uncertainty about when the pain will occur and about the effectiveness or not of the treatment prescribed to them, which is often poorly tolerated. The main objectives of this project are to be able to predict pain crises and to be able to know the expected effectiveness of a treatment designed specifically for migraine such as anti-CGRP monoclonal antibodies.

With this, the project will have a positive impact on several levels:

  • Population health: reduce the frequency and severity of attacks and achieve a conversion of patients with CM to ME, as well as prevent patients with ME from becoming chronic, significantly increasing the quality of life of patients with migraine.
  • Social impact: to reduce the great socioeconomic impact caused by migraine, by reducing absenteeism from work and loss of productivity associated with this disease.
  • SNS: reduce the number of consultations and pharmaceutical expenditure on futile treatments, contributing to a more efficient use of NHS resources.
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